HSP70 modulators and methods for making and using the same

ABSTRACT

The present invention provides compounds I and II and compositions thereof for use in the modulation of Hsp70. In some embodiments, the present invention provides a method for inhibiting Hsp70 activity. In some embodiments, the present invention provides a method of treating a subject suffering from or susceptible to a disease, disorder, or condition responsive to Hsp70 inhibition comprising administering to the subject a therapeutically effective amount of a provided compound. In some embodiments, the present invention provides a method for treating or preventing cancer in a subject suffering therefrom, comprising administering to a patient in need thereof a therapeutically effective amount of a provided compound.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application claims priority to U.S. provisional patentapplication No. 61/992,838, filed May 13, 2014, the entire contents ofwhich are hereby incorporated by reference.

BACKGROUND

The heat shock protein 70 (Hsp70) family members are powerful proteinswith major roles in malignancy, such as inhibition of apoptosis,induction of resistance to chemotherapy and regulation of the stabilityof onco-proteins. Specifically, Hsp70 expression blocks apoptosis atseveral levels, and in this respect the chaperone inhibits key effectorsof the apoptotic machinery, and also facilitates proteasome-mediateddegradation of apoptosis-regulatory proteins. The contribution of Hsp70isoforms to tumorigenesis is mainly through their role as co-chaperonesof heat shock protein 90 (Hsp90), a heat shock protein known to regulatethe transforming activities of several kinases and transcriptionfactors. In this process, Hsp70 initiates the association of the clientprotein with Hsp90 through a bridging protein called HSP-organizingprotein (HOP). These biological functions propose Hsp70 as an importanttarget whose inhibition or downregulation may result in significantapoptosis in a wide-range of cancer cells, and also in inhibition ofsignaling pathways involved in tumorigenesis and metastasis. Due tothese functions it is not surprising that Hsp70 is frequentlyoverexpressed in cancer, where the elevated expression is furthermorebelieved to be a cause of resistance to chemotherapy and othertreatments. These dual roles of Hsp70 in cancer, i.e. co-chaperone ofHsp90 and antiapoptotic molecule, suggest that inhibition of Hsp70 mayoffer a valuable anticancer strategy, as supported by Hsp70 knockdownstudies.

Much effort has recently been dedicated towards the discovery of Hsp70inhibitors and, unsurprisingly, molecules from a number of chemicalclasses have been reported to interact with Hsp70 through a variety ofmodes. These previous efforts have focused on either directly competingwith ATP, which achieves potency but limited cellular activity, or byallosteric mechanisms. While these molecules are reported to elicittheir effects through an Hsp70 mechanism, it is possible that they alsoact on multiple other unrelated and as yet unspecified mechanisms.Furthermore, these molecules tend to be hindered by a non-tractable SARwith subtle changes resulting in drastic changes in activity.

Hsp70 has proven to be a more difficult target to drug than Hsp90, whichcan be attributed to a number of reasons. Unlike Hsp90, there are nodrug-like natural products for which Hsp70-bound crystal structures areavailable to guide drug design. In addition, the nucleotide bindingpocket of Hsp70 is considerably more hydrophilic compared to that ofHsp90, requiring ATP to bind in a more extended conformation with polarcontacts deep within the binding pocket. Reversible competitiveinhibitors are particularly challenging to develop because of Hsp70'shigh affinity for ADP and high intracellular concentrations of ATP.While Hsp90 has proven highly amenable with numerous small-moleculeATP-competitive inhibitors entering into the clinic, to date no Hsp70inhibitors have entered clinical trials.

SUMMARY OF THE INVENTION

The present invention provides, among other things, novel compounds foruse in the modulation of Hsp70. In some embodiments, the presentinvention provides a compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein each variable isindependently as described in classes and subclasses herein, both singlyand in combination.

In some embodiments, the present invention provides a compound offormula II:

or a pharmaceutically acceptable salt thereof, wherein each variable isindependently as described in classes and subclasses herein, both singlyand in combination.

In certain embodiments, the present invention provides a pharmaceuticalcomposition comprising a compound of formula I and a pharmaceuticallyacceptable carrier. In some embodiments, the present invention providesa pharmaceutical composition, comprising of a compound of formula II anda pharmaceutically acceptable carrier.

In some embodiments, the present invention provides a method forinhibiting Hsp70 activity. In some embodiments, the present inventionprovides a method for inhibiting Hsp70 activity, comprising contactingHsp70 with a compound of formula I or a composition thereof. In someembodiments, the present invention provides a method for inhibitingHsp70 activity, comprising contacting Hsp70 with a compound of formulaII or a composition thereof. In some embodiments, the present inventionprovides a method for activating a caspase in cells. In someembodiments, the present invention provides a method for activating acaspase in cells, comprising administering to the cells a compound offormula I or a composition thereof. In some embodiments, the presentinvention provides a method for activating a caspase in cells,comprising administering to the cells a compound of formula II or acomposition thereof. In some embodiments, the present invention providesa method for inducing cell death. In some embodiments, the presentinvention provides a method for inducing cell death, comprisingadministering to the cells a compound of formula I or a compositionthereof. In some embodiments, the present invention provides a methodfor inducing cell death, comprising administering to the cells acompound of formula II or a composition thereof. In some embodiments,the present invention provides a method for inducing apoptosis. In someembodiments, the present invention provides a method for inducingapoptosis, comprising administering to the cells a compound of formula Ior a composition thereof. In some embodiments, the present inventionprovides a method for inducing apoptosis, comprising administering tothe cells a compound of formula II or a composition thereof. In someembodiments, the present invention provides a method for inhibiting cellgrowth. In some embodiments, the present invention provides a method forinhibiting cell growth, comprising administering to the cells a compoundof formula I or a composition thereof. In some embodiments, the presentinvention provides a method for inhibiting cell growth, comprisingadministering to the cells a compound of formula II or a compositionthereof. In some embodiments, the cells in a provided method areresistant to Hsp90 inhibitors.

In some embodiments, the present invention provides a method of treatinga subject suffering from or susceptible to a disease, disorder, orcondition responsive to Hsp70 inhibition comprising administering to thesubject a therapeutically effective amount of a compound of formula I ora composition thereof. In some embodiments, the present inventionprovides a method of treating a subject suffering from or susceptible toa disease, disorder, or condition responsive to Hsp70 inhibition,comprising administering to the subject a therapeutically effectiveamount of a compound of formula II or a composition thereof.

In some embodiments, the present invention provides a method fortreating or preventing cancer in a subject suffering therefrom. In someembodiments, the present invention provides a method for treating orpreventing cancer in a subject suffering therefrom, comprisingadministering to a patient in need thereof a therapeutically effectiveamount of a compound of formula I or a composition thereof. In someembodiments, the present invention provides a method for treating orpreventing cancer in a subject suffering therefrom, comprisingadministering to a patient in need thereof a therapeutically effectiveamount of a compound of formula II or a composition thereof. In someembodiments, a cancer in a provided method is refractory to treatmentwith Hsp90 inhibitors.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1. A: Hsp70 regulates several anti-apoptotic protein complexes;effects reverted by compound 32 treatment. MDA-MB-468 triple negativebreast cancer cells were treated with the Hsp70 inhibitor compound 32 orthe Hsp90 inhibitor PU-H71 and proteins were analyzed by Western blot.B: Compound 32 retains activity in diffuse large B-cell lymphoma (DLBCL)cells with induced resistance to PU-H71. C: The spectrum of PU-H71 andcompound 32—sensitive DLBCLs does not overlap.

DEFINITIONS

Certain compounds of the present disclosure, and definitions of specificfunctional groups are described in more detail below. For purposes ofthis disclosure, the chemical elements are identified in accordance withthe Periodic Table of the Elements, CAS version, Handbook of Chemistryand Physics, 75^(th) Ed., inside cover, and specific functional groupsare generally defined as described therein. Additionally, generalprinciples of organic chemistry, as well as specific functional moietiesand reactivity, are described in “Organic Chemistry”, Thomas Sorrell,University Science Books, Sausalito: 1999, the entire contents of whichare incorporated herein by reference.

As used herein, the following definitions shall apply unless otherwiseindicated.

The term “aliphatic” or “aliphatic group,” as used herein, means astraight-chain (i.e., unbranched) or branched, substituted orunsubstituted hydrocarbon chain that is completely saturated or thatcontains one or more units of unsaturation, or a monocyclic, bicyclic orpolycyclic hydrocarbon that is completely saturated or that contains oneor more units of unsaturation, but which is not aromatic (also referredto herein as “carbocycle,” “cycloaliphatic” or “cycloalkyl”), that has asingle point of attachment to the rest of the molecule. Unless otherwisespecified, aliphatic groups contain 1-20 aliphatic carbon atoms. In someembodiments, aliphatic groups contain 1-12 aliphatic carbon atoms. Insome embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms.In some embodiments, aliphatic groups contain 1-5 aliphatic carbonatoms. In other embodiments, aliphatic groups contain 1-4 aliphaticcarbon atoms. In still other embodiments, aliphatic groups contain 1-3aliphatic carbon atoms, and in yet other embodiments, aliphatic groupscontain 1-2 aliphatic carbon atoms. In some embodiments,“cycloaliphatic” (or “carbocycle” or “cycloalkyl”) refers to amonocyclic C₃-C₆ hydrocarbon that is completely saturated or thatcontains one or more units of unsaturation, but which is not aromatic,that has a single point of attachment to the rest of the molecule.Suitable aliphatic groups include, but are not limited to, linear orbranched, substituted or unsubstituted alkyl, alkenyl, alkynyl groupsand hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or(cycloalkyl)alkenyl.

The term “cycloaliphatic,” as used herein, refers to saturated orpartially unsaturated cyclic aliphatic monocyclic, bicyclic, orpolycyclic ring systems, as described herein, having from 3 to 14members, wherein the aliphatic ring system is optionally substituted asdefined above and described herein. Cycloaliphatic groups include,without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl,cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl,cyclooctenyl, norbornyl, adamantyl, and cyclooctadienyl. In someembodiments, the cycloalkyl has 3-6 carbons. The terms “cycloaliphatic,”may also include aliphatic rings that are fused to one or more aromaticor nonaromatic rings, such as decahydronaphthyl or tetrahydronaphthyl,where the radical or point of attachment is on the aliphatic ring. Insome embodiments, a carbocyclic group is bicyclic. In some embodiments,a carbocyclic group is tricyclic. In some embodiments, a carbocyclicgroup is polycyclic. In some embodiments, “cycloaliphatic” (or“carbocycle” or “cycloalkyl”) refers to a monocyclic C₃-C₆ hydrocarbon,or a C₈-C₁₀ bicyclic hydrocarbon that is completely saturated or thatcontains one or more units of unsaturation, but which is not aromatic,that has a single point of attachment to the rest of the molecule, or aC₉-C₁₆ tricyclic hydrocarbon that is completely saturated or thatcontains one or more units of unsaturation, but which is not aromatic,that has a single point of attachment to the rest of the molecule.

As used herein, the term “alkyl” is given its ordinary meaning in theart and may include saturated aliphatic groups, including straight-chainalkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic)groups, alkyl substituted cycloalkyl groups, and cycloalkyl substitutedalkyl groups. In certain embodiments, a straight chain or branched chainalkyl has about 1-20 carbon atoms in its backbone (e.g., C₁-C₂₀ forstraight chain, C₂-C₂₀ for branched chain), and alternatively, about1-10. In some embodiments, a cycloalkyl ring has from about 3-10 carbonatoms in their ring structure where such rings are monocyclic orbicyclic, and alternatively about 5, 6 or 7 carbons in the ringstructure. In some embodiments, an alkyl group may be a lower alkylgroup, wherein a lower alkyl group comprises 1-4 carbon atoms (e.g.,C₁-C₄ for straight chain lower alkyls).

As used herein, the term “haloalkyl” refers to an alkyl groupsubstituted with one or more halogen.

As used herein, the term “alkenyl” refers to an alkyl group, as definedherein, having one or more double bonds.

As used herein, the term “alkynyl” refers to an alkyl group, as definedherein, having one or more triple bonds.

The term “heteroalkyl” is given its ordinary meaning in the art andrefers to alkyl groups as described herein in which one or more carbonatoms is replaced with a heteroatom (e.g., oxygen, nitrogen, sulfur, andthe like). Examples of heteroalkyl groups include, but are not limitedto, alkoxy, poly(ethylene glycol)-, alkyl-substituted amino,tetrahydrofuranyl, piperidinyl, morpholinyl, etc.

The term “heteroatom” means one or more of oxygen, sulfur, nitrogen,phosphorus, or silicon (including, any oxidized form of nitrogen,sulfur, phosphorus, or silicon; the quaternized form of any basicnitrogen or; a substitutable nitrogen of a heterocyclic ring, forexample N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) orNR′ (as in N-substituted pyrrolidinyl)).

The term “unsaturated,” as used herein, means that a moiety has one ormore units of unsaturation.

The term “halogen” means F, Cl, Br, or I.

The term “aryl” used alone or as part of a larger moiety as in“aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic, bicyclicor polycyclic ring systems having a total of five to fourteen ringmembers, wherein at least one ring in the system is aromatic and whereineach ring in the system contains 3 to 7 ring members. The term “aryl”may be used interchangeably with the term “aryl ring.”

In certain embodiments of the present disclosure, “aryl” refers to anaromatic ring system which includes, but not limited to, phenyl,biphenyl, naphthyl, anthracyl and the like, which may bear one or moresubstituents. Also included within the scope of the term “aryl,” as itis used herein, is a group in which an aromatic ring is fused to one ormore non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl,phenanthridinyl, or tetrahydronaphthyl, and the like.

The terms “heteroaryl” and “heteroar-,” used alone or as part of alarger moiety, e.g., “heteroaralkyl,” or “heteroaralkoxy,” refer togroups having 5 to 14 ring atoms, preferably 5, 6, or 9 ring atoms;having 6, 10, or 14 π electrons shared in a cyclic array; and having, inaddition to carbon atoms, from one to five heteroatoms. The term“heteroatom” refers to nitrogen, oxygen, or sulfur, and includes anyoxidized form of nitrogen or sulfur, and any quaternized form of a basicnitrogen. Heteroaryl groups include, without limitation, thienyl,furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl,oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl,thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl,purinyl, naphthyridinyl, and pteridinyl. The terms “heteroaryl” and“heteroar-”, as used herein, also include groups in which aheteroaromatic ring is fused to one or more aryl, cycloaliphatic, orheterocyclyl rings, where the radical or point of attachment is on theheteroaromatic ring. Non-limiting examples include indolyl, isoindolyl,benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl,benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl,quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl,phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Aheteroaryl group may be mono- or bicyclic. The term “heteroaryl” may beused interchangeably with the terms “heteroaryl ring,” “heteroarylgroup,” or “heteroaromatic,” any of which terms include rings that areoptionally substituted. The terms “heteroaralkyl” and “heteroarylalkyl”refer to an alkyl group substituted by a heteroaryl moiety, wherein thealkyl and heteroaryl portions independently are optionally substituted.

As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclicradical,” and “heterocyclic ring” are used interchangeably and refer toa stable 3-to 14-membered monocyclic or 7-14-membered bicyclic orpolycyclic heterocyclic moiety that is either saturated or partiallyunsaturated, and having, in addition to carbon atoms, one or more,preferably one to four, heteroatoms, as defined above. When used inreference to a ring atom of a heterocycle, the term “nitrogen” includesa substituted nitrogen. As an example, in a saturated or partiallyunsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur ornitrogen, the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (asin pyrrolidinyl), or ⁺NR (as in N-substituted pyrrolidinyl).

A heterocyclic ring can be attached to its pendant group at anyheteroatom or carbon atom that results in a stable structure and any ofthe ring atoms can be optionally substituted. Examples of such saturatedor partially unsaturated heterocyclic radicals include, withoutlimitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl,piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl,diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. Theterms “heterocycle,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclicgroup,” “heterocyclic moiety,” and “heterocyclic radical,” are usedinterchangeably herein, and also include groups in which a heterocyclylring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings,such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, ortetrahydroquinolinyl, where the radical or point of attachment is on theheterocyclyl ring. A heterocyclyl group may be mono- or bicyclic. Theterm “heterocyclylalkyl” refers to an alkyl group substituted by aheterocyclyl, wherein the alkyl and heterocyclyl portions independentlyare optionally substituted.

As used herein, the term “partially unsaturated” refers to a ring moietythat includes at least one double or triple bond. The term “partiallyunsaturated” is intended to encompass rings having multiple sites ofunsaturation, but is not intended to include aryl or heteroarylmoieties, as herein defined.

In another aspect, the present disclosure provides “pharmaceuticallyacceptable” compositions, which comprise a therapeutically effectiveamount of one or more of the compounds described herein, formulatedtogether with one or more pharmaceutically acceptable carriers(additives) and/or diluents. As described in detail, the pharmaceuticalcompositions of the present disclosure may be specially formulated foradministration in solid or liquid form, including those adapted for thefollowing: oral administration, for example, drenches (aqueous ornon-aqueous solutions or suspensions), tablets, e.g., those targeted forbuccal, sublingual, and systemic absorption, boluses, powders, granules,pastes for application to the tongue; parenteral administration, forexample, by subcutaneous, intramuscular, intravenous or epiduralinjection as, for example, a sterile solution or suspension, orsustained-release formulation; topical application, for example, as acream, ointment, or a controlled-release patch or spray applied to theskin, lungs, or oral cavity; intravaginally or intrarectally, forexample, as a pessary, cream or foam; sublingually; ocularly;transdermally; or nasally, pulmonary and to other mucosal surfaces.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The phrase “pharmaceutically acceptable carrier” as used herein means apharmaceutically-acceptable material, composition or vehicle, such as aliquid or solid filler, diluent, excipient, or solvent encapsulatingmaterial, involved in carrying or transporting the subject compound fromone organ, or portion of the body, to another organ, or portion of thebody. Each carrier must be “acceptable” in the sense of being compatiblewith the other ingredients of the formulation and not injurious to thepatient. Some examples of materials which can serve aspharmaceutically-acceptable carriers include: sugars, such as lactose,glucose and sucrose; starches, such as corn starch and potato starch;cellulose, and its derivatives, such as sodium carboxymethyl cellulose,ethyl cellulose and cellulose acetate; powdered tragacanth; malt;gelatin; talc; excipients, such as cocoa butter and suppository waxes;oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil,olive oil, corn oil and soybean oil; glycols, such as propylene glycol;polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol;esters, such as ethyl oleate and ethyl laurate; agar; buffering agents,such as magnesium hydroxide and aluminum hydroxide; alginic acid;pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol;pH buffered solutions; polyesters, polycarbonates and/or polyanhydrides;and other non-toxic compatible substances employed in pharmaceuticalformulations.

Unless otherwise stated, structures depicted herein are also meant toinclude all isomeric (e.g., enantiomeric, diastereomeric, and geometric(or conformational)) forms of the structure; for example, the R and Sconfigurations for each stereocenter, Z and E double bond isomers, and Zand E conformational isomers. Therefore, single stereochemical isomersas well as enantiomeric, diastereomeric, and geometric (orconformational) mixtures of the present compounds are within the scopeof the disclosure. Unless otherwise stated, all tautomeric forms of thecompounds of the disclosure are within the scope of the disclosure.

If, for instance, a particular enantiomer of a compound of the presentdisclosure is desired, it may be prepared by asymmetric synthesis,chiral chromatography, or by derivation with a chiral auxiliary, wherethe resulting diastereomeric mixture is separated and the auxiliarygroup cleaved to provide the pure desired enantiomers. Alternatively,where the molecule contains a basic functional group, such as amino, oran acidic functional group, such as carboxyl, diastereomeric salts areformed with an appropriate optically-active acid or base, followed byresolution of the diastereomers thus formed by fractionalcrystallization or chromatographic means well known in the art, andsubsequent recovery of the pure enantiomers.

Additionally, unless otherwise stated, structures depicted herein arealso meant to include compounds that differ only in the presence of oneor more isotopically enriched atoms. For example, compounds having thepresent structures including the replacement of hydrogen by deuterium ortritium, or the replacement of a carbon by a 13C- or 14C-enriched carbonare within the scope of this disclosure. Such compounds are useful, forexample, as analytical tools, as probes in biological assays, or astherapeutic agents in accordance with the present disclosure.

One of ordinary skill in the art will appreciate that the syntheticmethods, as described herein, utilize a variety of protecting groups. Bythe term “protecting group,” as used herein, it is meant that aparticular functional moiety, e.g., O, S, or N, is masked or blocked,permitting, if desired, a reaction to be carried out selectively atanother reactive site in a multifunctional compound. In preferredembodiments, a protecting group reacts selectively in good yield to givea protected substrate that is stable to the projected reactions; theprotecting group is preferably selectively removable by readilyavailable, preferably non-toxic reagents that do not attack the otherfunctional groups; the protecting group forms a separable derivative(more preferably without the generation of new stereogenic centers); andthe protecting group will preferably have a minimum of additionalfunctionality to avoid further sites of reaction. As detailed herein,oxygen, sulfur, nitrogen, and carbon protecting groups may be utilized.By way of non-limiting example, hydroxyl protecting groups includemethyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl,(phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM),p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM),guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM),siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl,bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR),tetrahydropyranyl (THP), 3-bromotetrahydropyranyl,tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl(MTHP), 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranylS,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl(CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl,2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl,1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl,1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl,2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl,t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl,benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl,p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl,p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxido,diphenylmethyl, p,p′-dinitrobenzhydryl, 5-dibenzosuberyl,triphenylmethyl, α-naphthyldiphenylmethyl,p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl,tri(p-methoxyphenyl)methyl, 4-(4′-bromophenacyloxyphenyl)diphenylmethyl,4,4′,4″-tris(4,5-dichlorophthalimidophenyl)methyl,4,4′,4″-tris(levulinoyloxyphenyl)methyl,4,4′,4″-tris(benzoyloxyphenyl)methyl,3-(imidazol-1-yl)bis(4′,4″-dimethoxyphenyl)methyl,1,1-bis(4-methoxyphenyl)-1′-pyrenylmethyl, 9-anthryl,9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl,1,3-benzodithiolan-2-yl, benzisothiazolyl S,S-dioxido, trimethylsilyl(TMS), triethylsilyl (TES), triisopropylsilyl (TIPS),dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS),dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl(TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl,diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate,benzoylformate, acetate, chloroacetate, dichloroacetate,trichloroacetate, trifluoroacetate, methoxyacetate,triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate,3-phenylpropionate, 4-oxopentanoate (levulinate),4,4-(ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate,adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate,2,4,6-trimethylbenzoate (mesitoate), alkyl methyl carbonate,9-fluorenylmethyl carbonate (Fmoc), alkyl ethyl carbonate, alkyl2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate(TMSEC), 2-(phenylsulfonyl) ethyl carbonate (Psec),2-(triphenylphosphonio) ethyl carbonate (Peoc), alkyl isobutylcarbonate, alkyl vinyl carbonate alkyl allyl carbonate, alkylp-nitrophenyl carbonate, alkyl benzyl carbonate, alkyl p-methoxybenzylcarbonate, alkyl 3,4-dimethoxybenzyl carbonate, alkyl o-nitrobenzylcarbonate, alkyl p-nitrobenzyl carbonate, alkyl S-benzyl thiocarbonate,4-ethoxy-1-napththyl carbonate, methyl dithiocarbonate, 2-iodobenzoate,4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate,2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl,4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate,2,6-dichloro-4-methylphenoxyacetate,2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate,2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate,isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate,o-(methoxycarbonyl)benzoate, a-naphthoate, nitrate, alkylN,N,N′,N′-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate,borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate,sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate(Ts).

For protecting 1,2- or 1,3-diols, the protecting groups includemethylene acetal, ethylidene acetal, 1-t-butylethylidene ketal,1-phenylethylidene ketal, (4-methoxyphenyl)ethylidene acetal,2,2,2-trichloroethylidene acetal, acetonide, cyclopentylidene ketal,cyclohexylidene ketal, cycloheptylidene ketal, benzylidene acetal,p-methoxybenzylidene acetal, 2,4-dimethoxybenzylidene ketal,3,4-dimethoxybenzylidene acetal, 2-nitrobenzylidene acetal,methoxymethylene acetal, ethoxymethylene acetal, dimethoxymethyleneortho ester, 1-methoxyethylidene ortho ester, 1-ethoxyethylidine orthoester, 1,2-dimethoxyethylidene ortho ester, α-methoxybenzylidene orthoester, 1-(N,N-dimethylamino)ethylidene derivative,α-(N,N′-dimethylamino)benzylidene derivative, 2-oxacyclopentylideneortho ester, di-t-butylsilylene group (DTBS),1,3-(1,1,3,3-tetraisopropyldisiloxanylidene) derivative (TIPDS),tetra-t-butoxydisiloxane-1,3-diylidene derivative (TBDS), cycliccarbonates, cyclic boronates, ethyl boronate, and phenyl boronate.

Amino-protecting groups include methyl carbamate, ethyl carbamante,9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethylcarbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate,2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methylcarbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc),2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate(Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1-methylethylcarbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate,1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC),1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC),1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc),1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate (t-Bumeoc), 2-(2′- and4′-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethylcarbamate, t-butyl carbamate (BOC), 1-adamantyl carbamate (Adoc), vinylcarbamate (Voc), allyl carbamate (Alloc), 1-isopropylallyl carbamate(Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc),8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithiocarbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz),p-nitobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzylcarbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzylcarbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate,2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate,2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3-dithianyl)]methylcarbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc),2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate(Peoc), 2-triphenylphosphonioisopropyl carbamate (Ppoc),1,1-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate,p-(dihydroxyboryl)benzyl carbamate, 5-benzisoxazolylmethyl carbamate,2-(trifluoromethyl)-6-chromonylmethyl carbamate (Tcroc), m-nitrophenylcarbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate,3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl(o-nitrophenyl)methylcarbamate, phenothiazinyl-(10)-carbonyl derivative,N′-p-toluenesulfonylaminocarbonyl derivative, N′-phenylaminothiocarbonylderivative, t-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzylcarbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentylcarbamate, cyclopropylmethyl carbamate, p-decyloxybenzyl carbamate,2,2-dimethoxycarbonylvinyl carbamate, o-(N,N-dimethylcarboxamido)benzylcarbamate, 1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl carbamate,1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate,2-furanylmethyl carbamate, 2-iodoethyl carbamate, isoborynl carbamate,isobutyl carbamate, isonicotinyl carbamate,p-(p′-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate,1-methylcyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate,1-methyl-1-(3,5-dimethoxyphenyl)ethyl carbamate,1-methyl-1-(p-phenylazophenyl)ethyl carbamate, 1-methyl-1-phenylethylcarbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate,p-(phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate,4-(trimethylammonium)benzyl carbamate, 2,4,6-trimethylbenzyl carbamate,formamide, acetamide, chloroacetamide, trichloroacetamide,trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide,3-pyridylcarboxamide, N-benzoylphenylalanyl derivative, benzamide,p-phenylbenzamide, o-nitophenylacetamide, o-nitrophenoxyacetamide,acetoacetamide, (N′-dithiobenzyloxycarbonylamino)acetamide,3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide,2-methyl-2-(o-nitrophenoxy)propanamide,2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide,3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethioninederivative, o-nitrobenzamide, o-(benzoyloxymethyl)benzamide,4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts),N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole,N-1,1,4,4-tetramethyldisilylazacyclopentane adduct (STABASE),5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted3,5-dinitro-4-pyridone, N-methylamine, N-allylamine,N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine,N-(1-isopropyl-4-nitro-2-oxo-3-pyroolin-3-yl)amine, quaternary ammoniumsalts, N-benzylamine, N-di(4-methoxyphenyl)methylamine,N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr),N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr),N-9-phenylfluorenylamine (PhF),N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm),N-2-picolylamino N′-oxide, N-1,1-dimethylthiomethyleneamine,N-benzylideneamine, N-p-methoxybenzylideneamine,N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine,N-(N′,N′-dimethylaminomethylene)amine, N,N′-isopropylidenediamine,N-p-nitrobenzylideneamine, N-salicylideneamine,N-5-chlorosalicylideneamine,N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine,N-cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine,N-borane derivative, N-diphenylborinic acid derivative,N-[phenyl(pentacarbonylchromium- or tungsten)carbonyl]amine, N-copperchelate, N-zinc chelate, N-nitroamine, N-nitrosoamine, amine N-oxide,diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt),diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzylphosphoramidate, diphenyl phosphoramidate, benzenesulfenamide,o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide,pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide,triphenylmethylsulfenamide, 3-nitropyridinesulfenamide (Npys),p-toluenesulfonamide (Ts), benzenesulfonamide,2,3,6,-trimethyl-4-methoxybenzenesulfonamide (Mtr),2,4,6-trimethoxybenzenesulfonamide (Mtb),2,6-dimethyl-4-methoxybenzenesulfonamide (Pme),2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte),4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide(Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds),2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide(Ms), β-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide,4-(4′,8′-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS),benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.Exemplary protecting groups are detailed herein, however, it will beappreciated that the present disclosure is not intended to be limited tothese protecting groups; rather, a variety of additional equivalentprotecting groups can be readily identified using the above criteria andutilized in the method of the present disclosure. Additionally, avariety of protecting groups are well known in the art and include thosedescribed in detail in Protecting Groups in Organic Synthesis, T. W.Greene and P. G. M. Wuts, 3^(rd) edition, John Wiley & Sons, 1999, theentirety of which is incorporated herein by reference.

As described herein, compounds of the disclosure may contain “optionallysubstituted” moieties. In general, the term “substituted,” whetherpreceded by the term “optionally” or not, means that one or morehydrogens of the designated moiety are replaced with a suitablesubstituent. Unless otherwise indicated, an “optionally substituted”group may have a suitable substituent at each substitutable position ofthe group, and when more than one position in any given structure may besubstituted with more than one substituent selected from a specifiedgroup, the substituent may be either the same or different at everyposition. Combinations of substituents envisioned by this disclosure arepreferably those that result in the formation of stable or chemicallyfeasible compounds. The term “stable,” as used herein, refers tocompounds that are not substantially altered when subjected toconditions to allow for their production, detection, and, in certainembodiments, their recovery, purification, and use for one or more ofthe purposes disclosed herein.

Unless otherwise indicated, suitable monovalent substituents on asubstitutable carbon atom of an “optionally substituted” group areindependently halogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl.

When used as a chemical bond, “

” shall be understood to depict a single carbon-carbon bond withundefined stereochemistry at a carbon center. Thus, a substituentattached to a carbon atom with a “

” bond refers to embodiments where the substituent is coming out of theplane of the paper, embodiments where the substituent is going behindthe plane of the paper, and combinations (i.e., stereochemical mixtures)thereof.

As used herein and in the claims, the singular forms “a”, “an”, and“the” include the plural reference unless the context clearly indicatesotherwise. Thus, for example, a reference to “a compound” includes aplurality of such compounds.

The phrases “parenteral administration” and “administered parenterally”as used herein means modes of administration other than enteral andtopical administration, usually by injection, and includes, withoutlimitation, intravenous, intramuscular, intraarterial, intrathecal,intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal,transtracheal, subcutaneous, subcuticular, intraarticulare, subcapsular,subarachnoid, intraspinal and intrasternal injection and infusion.

As used herein, the term “therapeutically effective amount” means anamount of a substance (e.g., a therapeutic agent, composition, and/orformulation) that elicits a desired biological response whenadministered as part of a therapeutic regimen. In some embodiments, atherapeutically effective amount of a substance is an amount that issufficient, when administered to a subject suffering from or susceptibleto a disease, disorder, and/or condition, to treat the disease,disorder, and/or condition. As will be appreciated by those of ordinaryskill in this art, the effective amount of a substance may varydepending on such factors as the desired biological endpoint, thesubstance to be delivered, the target cell or tissue, etc. For example,the effective amount of compound in a formulation to treat a disease,disorder, and/or condition is the amount that alleviates, ameliorates,relieves, inhibits, prevents, delays onset of, reduces severity ofand/or reduces incidence of one or more symptoms or features of thedisease, disorder, and/or condition. In some embodiments, atherapeutically effective amount is administered in a single dose; insome embodiments, multiple unit doses are required to deliver atherapeutically effective amount.

As used herein, the term “treat,” “treatment,” or “treating” refers toany method used to partially or completely alleviate, ameliorate,relieve, inhibit, prevent, delay onset of, reduce severity of and/orreduce incidence of one or more symptoms or features of a disease,disorder, and/or condition. Treatment may be administered to a subjectwho does not exhibit signs of a disease, disorder, and/or condition. Insome embodiments, treatment may be administered to a subject whoexhibits only early signs of the disease, disorder, and/or condition forthe purpose of decreasing the risk of developing pathology associatedwith the disease, disorder, and/or condition.

The expression “unit dose” as used herein refers to a physicallydiscrete unit of a formulation appropriate for a subject to be treated.It will be understood, however, that the total daily usage of aformulation of the present invention will be decided by the attendingphysician within the scope of sound medical judgment. The specificeffective dose level for any particular subject or organism may dependupon a variety of factors including the disorder being treated and theseverity of the disorder; activity of specific active compound employed;specific composition employed; age, body weight, general health, sex anddiet of the subject; time of administration, and rate of excretion ofthe specific active compound employed; duration of the treatment; drugsand/or additional therapies used in combination or coincidental withspecific compound(s) employed, and like factors well known in themedical arts. A particular unit dose may or may not contain atherapeutically effective amount of a therapeutic agent.

An individual who is “suffering from” a disease, disorder, and/orcondition has been diagnosed with and/or displays one or more symptomsof the disease, disorder, and/or condition.

An individual who is “susceptible to” a disease, disorder, and/orcondition has not been diagnosed with the disease, disorder, and/orcondition. In some embodiments, an individual who is susceptible to adisease, disorder, and/or condition may exhibit symptoms of the disease,disorder, and/or condition. In some embodiments, an individual who issusceptible to a disease, disorder, and/or condition may not exhibitsymptoms of the disease, disorder, and/or condition. In someembodiments, an individual who is susceptible to a disease, disorder,and/or condition will develop the disease, disorder, and/or condition.In some embodiments, an individual who is susceptible to a disease,disorder, and/or condition will not develop the disease, disorder,and/or condition.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

The present invention encompasses the recognition that the design ofpotent and effective modulators of Hsp70 is a challenging endeavor giventhe lack of natural products known to bind Hsp70, and the generalcompetitive and binding pocket difficulties faced by candidatemodulators, particularly in the case of reversible Hsp70 modulators.

The present invention provides, among other things, novel compounds foruse in the modulation of Hsp70. In some embodiments, the presentinvention provides unexpectedly effective reversible inhibitors ofHsp70. Certain irreversible pyrimidine-based derivatives have beenpreviously shown to selectively bind Hsp70 present in cancer cells,induce degradation of Hsp90/Hsp70 complex oncoclient proteins withoutfeedback induction of Hsp70, and induce apoptosis (see, for example, WO2011/022440). However, prior to the present invention, pyrimidine-basedcompounds have not been demonstrated to show activity in certain Hsp70model systems below a concentration of about 1.0 uM. The presentinvention surprisingly provides compounds that show activity in suchmodel systems at concentrations below about 1.0 uM. In some embodiments,provided compounds show activity in such model systems at concentrationsbelow about 0.5 uM. In some embodiments, provided compounds showactivity in such model systems at concentrations below about 0.4 uM. Insome embodiments, provided compounds show activity in such model systemsat concentrations below about 0.2 uM. In some embodiments, providedcompounds show activity in such model systems at concentrations belowabout 0.1 uM. In some embodiments, provided compounds show activity insuch model systems at concentrations below about 0.01 uM. In someembodiments, a model system in which provided compounds show theseactivities is a caspase cleavage assay.

In some embodiments, a provided compound of the present inventionselectively inhibits Hsp70 in tumor cells. In some embodiments, aprovided compound selectively inhibits tumor-specific Hsp70 and/or Hsp70complexes. Assays for testing selective inhibition of tumor-specificHsp70 and/or Hsp70 complexes are widely known in the art, including butnot limited to those described in WO 2011/022440.

In certain embodiments, the present invention provides compounds offormula I:

or a pharmaceutically acceptable salt thereof, wherein:

-   -   X is —N═ or —CH═;    -   X¹ is —N═ or —C(R⁵)═;    -   R¹ is

-   -   R^(1a) is

or C₁₋₆ aliphatic optionally substituted with one or more groupsindependently selected from —OH, cyclopropyl, or 5-membered heteroarylhaving 1-2 heteroatoms independently selected from nitrogen, oxygen orsulfur;

-   -   each R^(1b) is independently hydrogen, C₁₋₄ alkyl, or two R^(1b)        groups are optionally taken together to form an oxo group;    -   each of R^(1c) and R^(1d) is independently hydrogen or C₁₋₄        alkyl;    -   R² is —O—CH₂-Ring A, —NH—CH₂-Ring A, or —O—CH₂CH₂-Ring A;    -   Ring A is unsubstituted phenyl, unsubstituted furanyl,

or pyridinyl optionally substituted with R^(A5);

-   -   each of R^(A1) is independently halogen, —CN, —C(O)N(R)₂,        —N(R)₂, —OR, —C(O)R, —N₃, an optionally substituted 5- or        6-membered heterocyclyl or heteroaryl having one or two        heteroatoms independently selected from nitrogen, oxygen, or        sulfur, or C₁₋₄ alkyl optionally substituted with one or more        halogen;    -   each R is independently hydrogen or C₁₋₄ alkyl optionally        substituted with one or more halogen;    -   R^(A2) is —Cl, —Br, —I, —CN, —C(O)N(R)₂, —N(R)₂, —OR, —C(O)R,        —N₃, an optionally substituted 5- or 6-membered heterocyclyl or        heteroaryl having one or two heteroatoms independently selected        from nitrogen, oxygen or sulfur, or C₁₋₄ alkyl optionally        substituted with one or more halogen;    -   n is 1 to 4;    -   R^(A3) is —H or —F;    -   R^(A4) is —F or —OR;    -   R^(A5) is —OR or —N(R)₂;    -   R³ is —C(O)N(R^(3a))₂, —OR^(3b), —C(O)H, —C(O)OR, or        —N(R^(3c))₂;    -   each R^(3a) is independently hydrogen or C₁ alkyl optionally        substituted with one or more groups independently selected from        halogen or 1-pyrrolidinyl;    -   R^(3b) is hydrogen or C₁₋₄ alkyl optionally substituted with one        or more groups independently selected from halogen, C₁₋₄ alkyl,        C₁₋₄ haloalkyl, oxo, or —N(R)₂;    -   each R^(3c) is independently hydrogen or C₁₋₄ alkyl optionally        substituted with one or more groups independently selected from        halogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, oxo, or —N(R)₂;    -   R⁴ is R, halogen, or —N(R)₂; and    -   R⁵ is hydrogen, methyl or —N(R)₂.

In certain embodiments, provided compounds of formula I have an activityin a caspase cleaving assay (e.g., measured as the concentration of acompound required to achieve 50% of maximum caspase cleavage) belowabout 1.0 μM. In certain embodiments, provided compounds of formula Ihave an activity in a caspase cleaving assay below about 0.5 μM. Incertain embodiments, provided compounds of formula I have an activity ina caspase cleaving assay below about 0.4 μM. In certain embodiments,provided compounds of formula I have an activity in a caspase cleavingassay below about 0.2 μM. In certain embodiments, provided compounds offormula I have an activity in a caspase cleaving assay below about 0.1μM. In certain embodiments, provided compounds of formula I have anactivity in a caspase cleaving assay below about 0.01 μM.

In certain embodiments, the present invention provides compounds offormula II:

or a pharmaceutically acceptable salt thereof, wherein:

-   -   Y is —S—, —O—, or —CR₂—;    -   R¹ is

-   -   R^(1a) is

or C₁₋₆ aliphatic optionally substituted with one or more groupsindependently selected from —OH, cyclopropyl, or 5-membered heteroarylhaving 1-2 heteroatoms independently selected from nitrogen, oxygen, orsulfur;

-   -   each R^(1b) is independently hydrogen, C₁₋₄ alkyl, or two R^(1b)        groups are optionally taken together to form an oxo group;    -   each of R^(1c) and R^(1d) is independently hydrogen or C₁₋₄        alkyl;    -   R² is —O—CH₂-Ring A, —NH—CH₂-Ring A, or —O—CH₂CH₂-Ring A;    -   Ring A is unsubstituted phenyl, unsubstituted furanyl,

or pyridinyl optionally substituted with R^(A5);

-   -   each of R^(A1) is independently halogen, —CN, —C(O)N(R)₂,        —N(R)₂, —OR, —C(O)R, —N₃, an optionally substituted 5- or        6-membered heterocyclyl or heteroaryl having one or two        heteroatoms independently selected from nitrogen, oxygen, or        sulfur, or C₁₋₄ alkyl optionally substituted with one or more        halogen;    -   each R is independently hydrogen or C₁₋₄ alkyl optionally        substituted with one or more halogen;    -   R^(A2) is —Cl, —Br, —I, —CN, —C(O)N(R)₂, —N(R)₂, —OR, —C(O)R,        —N₃, an optionally substituted 5- or 6-membered heterocyclyl or        heteroaryl having one or two heteroatoms independently selected        from nitrogen, oxygen or sulfur, or C₁₋₄ alkyl optionally        substituted with one or more halogen;    -   n is 1 to 4;    -   R^(A3) is —H or —F;    -   R^(A4) is —F or —OR;    -   R^(A5) is —OR or —N(R)₂; and    -   Ring B is

thienyl optionally substituted with —C(O)R, or furanyl optionallysubstituted with —C(O)R.

In certain embodiments, provided compounds of formula II have anactivity in a caspase cleaving assay below about 1.0 μM. In certainembodiments, provided compounds of formula II have an activity in acaspase cleaving assay below about 0.5 μM. In certain embodiments,provided compounds of formula II have an activity in a caspase cleavingassay below about 0.4 μM. In certain embodiments, provided compounds offormula II have an activity in a caspase cleaving assay below about 0.2μM. In certain embodiments, provided compounds of formula II have anactivity in a caspase cleaving assay below about 0.1 μM. In certainembodiments, provided compounds of formula II have an activity in acaspase cleaving assay below about 0.01 μM.

In some embodiments, X is —N═. In some embodiments, X is —CH═.

In some embodiments, X¹ is —N═. In some embodiments, X is —C(R⁵)═. Insome embodiments, X is —C(R⁵)═, wherein R⁵ is hydrogen. In someembodiments, X is —C(R⁵)═, wherein R⁵ is methyl. In some embodiments, Xis —C(R⁵)═, wherein R⁵ is —N(R)₂. In some embodiments, X is —C(R⁵)═,wherein R⁵ is —NH₂.

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, each R^(1b) is hydrogen. In some embodiments, R¹ is

In some embodiments, R¹ is

wherein each R^(1b) is independently C₁₋₄ alkyl. In some embodiments,two R^(1b) are taken together to form an oxo group. In some embodiments,R¹ is

In some embodiments, R¹ is

In some embodiments, R^(1a) is

In some embodiments, R^(1a) is C₁₋₆ aliphatic optionally substitutedwith one or more groups independently selected from —OH, cyclopropyl, or5-membered heteroaryl having 1-2 heteroatoms independently selected fromnitrogen, oxygen or sulfur. In some embodiments, R^(1a) is C₁₋₆ straightchain aliphatic optionally substituted with one or more groupsindependently selected from —OH, cyclopropyl, or 5-membered heteroarylhaving 1-2 heteroatoms independently selected from nitrogen, oxygen orsulfur. In some embodiments, R^(1a) is C₁₋₆ straight chain aliphaticoptionally substituted with one group independently selected from —OH,cyclopropyl, or 5-membered heteroaryl having 1-2 heteroatomsindependently selected from nitrogen, oxygen or sulfur.

In some embodiments, R^(1a) is C₁₋₆ aliphatic. In some embodiments,R^(1a) is straight-chain C₁₋₆ aliphatic. In some embodiments, R^(1a) isstraight-chain C₁₋₆ alkyl. In some embodiments, R^(1a) is methyl. Insome embodiments, R^(1a) is straight-chain alkenyl. In some embodiments,R^(1a) is —CH₂CH═CH₂. In some embodiments, R^(1a) is straight-chain C₁₋₆alkynyl. In some embodiments, R^(1a) is —(CH₂)_(n)C≡CH, wherein n is1-4. In some embodiments, R^(1a) is —CH₂C≡CH. In some embodiments,R^(1a) is —(CH₂)₃C≡CH. In some embodiments, R^(1a) is —(CH₂)₄C≡CH. Insome embodiments, R^(1a) is —CH₂C≡CCH₂OH.

In some embodiments, R^(1a) is branched chain C₁₋₆ aliphatic. In someembodiments, R^(1a) is branched chain alkynyl. In some embodiments,R^(1a) is branched chain alkynyl with a terminal —C≡CH group. In someembodiments, R^(1a) is —CH(CH₃)C≡CH. In some embodiments, R^(1a) isisopropyl.

In some embodiments, R^(1a) is C₁₋₆ straight chain aliphatic substitutedwith one group independently selected from —OH, cyclopropyl, or5-membered heteroaryl having 1-2 heteroatoms independently selected fromnitrogen, oxygen or sulfur. In some embodiments, R^(1a) is methylsubstituted with a cyclopropyl group, or a 5-membered heteroaryl having1-2 heteroatoms independently selected nitrogen, oxygen or sulfur. Insome embodiments, R^(1a) is methyl substituted with cyclopropyl. In someembodiments, R^(1a) is methyl substituted with a 5-membered heteroarylhaving 1-2 heteroatoms independently selected nitrogen, oxygen orsulfur. In some embodiments, R^(1a) is methyl substituted with

In some embodiments, R^(1a) is methyl substituted with

In some embodiments, R^(1a) is methyl substituted with

In some embodiments, R^(1a) is 2-hydroxyethyl.

In some embodiments, R^(1a) is C₁₋₆ cycloaliphatic. In some embodiments,R^(1a) is cyclopropyl.

In some embodiments, R^(1a) is selected from methyl, 2-hydroxyethyl,—CH₂C≡CH, —(CH₂)₃C≡CH, —(CH₂)₄C≡CH, —CH(CH₃)C≡CH, isopropyl, —CH₂CH≡CH₂,

cyclopropyl,

In some embodiments, R^(1a) is selected from methyl, 2-hydroxyethyl,—CH₂C≡CH, —(CH₂)₃C≡CH, —(CH₂)₄C≡CH, —CH(CH₃)C≡CH, isopropyl, —CH₂CH═CH₂,

cyclopropyl,

In some embodiments, R^(1a) is selected from methyl, 2-hydroxyethyl,—CH₂C≡CH, —(CH₂)₃C≡CH, —(CH₂)₄C≡CH, —CH(CH₃)C≡CH, —CH₂CH═CH₂,

cyclopropyl,

In some embodiments, R^(1a) is selected from methyl, 2-hydroxyethyl,—CH₂C≡CH, —(CH₂)₃C≡CH, —(CH₂)₄C≡CH, —CH(CH₃)C≡CH, —CH₂CH═CH₂,

cyclopropyl,

In some embodiments, R^(1a) does not place a quaternary carbon adjacentto the piperazine nitrogen attachment point.

In some embodiments, each R^(1b) is independently hydrogen, or twoR^(1b) groups are optionally taken together to form an oxo group. Insome embodiments, each R^(1b) is hydrogen.

In some embodiments, R^(1b) is C₁₋₄ alkyl. In some embodiments, eachR^(1b) is C₁₋₄ alkyl. In some embodiments, each R^(1b) is methyl. Insome embodiments, R¹ is

Insome embodiments, R¹ is

In some embodiments, two R^(1b) groups are optionally taken together toform an oxo group.

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, each R^(1c) is independently hydrogen or C₁₋₄alkyl. In some embodiments, R^(1c) is hydrogen. In some embodiments,R^(1c) is C₁₋₄ alkyl. In some embodiments, R^(1c) is methyl. In someembodiments, each R^(1c) is hydrogen. In some embodiments, one R^(1c) ishydrogen, and the other R^(1c) is C₁₋₄ alkyl. In some embodiments, eachR^(1c) is independently C₁₋₄ alkyl. In some embodiments, each R^(1c) ismethyl. In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R^(1d) is hydrogen or C₁₋₄ alkyl. In someembodiments, R^(1d) is hydrogen. In some embodiments, R^(1d) is C₁₋₄alkyl. In some embodiments, R^(1d) is methyl. In some embodiments, eachR^(1c) is independently hydrogen or C₁₋₄ alkyl, and each R^(1d) isindependently C₁₋₄ alkyl.

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is

wherein each of R^(1c) and R^(1d) is independently hydrogen or C₁₋₄alkyl.

In some embodiments, each of R^(1c) and R^(1d) is hydrogen. In someembodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R^(1c) is hydrogen or C₁₋₄ alkyl, and R^(1d) isC₁₋₄ alkyl. In some embodiments, R¹ is

wherein R^(1c) is hydrogen or C₁₋₄ alkyl, and R^(1d) is C₁₋₄ alkyl. Insome embodiments, R¹ is

wherein R^(1c) is hydrogen or C₁₋₄ alkyl, and R^(1d) is C₁₋₄ alkyl. Insome embodiments, R¹ is

wherein R^(1c) is hydrogen or C₁₋₄ alkyl, and R^(1d) is C₁₋₄ alkyl.

In some embodiments, R^(1c) is hydrogen, and R^(1d) is C₁₋₄ alkyl. Insome embodiments, R¹ is

wherein R^(1c) is hydrogen, and R^(1d) is C₁₋₄ alkyl. In someembodiments, R¹ is

wherein R^(1c) is hydrogen, and R^(1d) is C₁₋₄ alkyl. In someembodiments, R¹ is

wherein R^(1c) is hydrogen, and R^(1d) is C₁₋₄ alkyl. In someembodiments, R^(1c) is hydrogen, and R^(1d) is methyl. In someembodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, each of R^(1c) and R^(1d) is independently C₁₋₄alkyl. In some embodiments, R¹ is

herein each of R^(1c) and R^(1d) is independently C₁₋₄ alkyl. In someembodiments, R¹ is

wherein each of R^(1c) and R^(1d) is independently C₁₋₄ alkyl. In someembodiments, R¹ is

wherein each of R^(1c) and R^(1d) is independently C₁₋₄ alkyl. In someembodiments, R^(1c) and R^(1d) are methyl. In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is

Exemplary R¹ groups are depicted below:

In some embodiments, R¹ is selected from a group in Table 1, below.

TABLE 1 Exemplary R1 groups.

In some embodiments, R² is —O—CH₂-Ring A, —NH—CH₂-Ring A, or—O—CH₂CH₂-Ring A. In some embodiments, R² is —O—CH₂-Ring A. In someembodiments, R² is —NH—CH₂-Ring A. In some embodiments, R² is—O—CH₂CH₂-Ring A.

In some embodiments, Ring A is unsubstituted phenyl. In someembodiments, Ring A is unsubstituted furanyl. In some embodiments, RingA is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is pyridinyl optionally substituted withR^(A5).

In some embodiments, Ring A is phenyl. In some embodiments, Ring A is—C₆D₅. In some embodiments, R² is

In some embodiments, R² is

In some embodiments, R² is

In some embodiments, Ring A is furanyl. In some embodiments, Ring A is1-furanyl. In some embodiments, Ring A is 2-furanyl. In someembodiments, R² is

In some embodiments, R² is

In some embodiments, Ring A is

In some embodiments, each of R^(A1) is independently halogen, —CN,—C(O)N(R)₂, —N(R)₂, —OR, —C(O)R, —N₃, an optionally substituted 5- or6-membered heterocyclyl or heteroaryl having one or two heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or C₁₋₄ alkyloptionally substituted with one or more halogen. In some embodiments,each of R^(A1) is independently halogen, —CN, —C(O)N(R)₂, —N(R)₂, —OR,—C(O)R, —N₃, a 5- or 6-membered heterocyclyl or heteroaryl having one ortwo heteroatoms independently selected from nitrogen, oxygen, or sulfur,or C₁₋₄ alkyl optionally substituted with one or more halogen. In someembodiments, each of R^(A1) is independently halogen, —CN, —C(O)N(R)₂,—N(R)₂, —OR, —C(O)R, —N₃, or C₁₋₄ alkyl optionally substituted with oneor more halogen. In some embodiments, each of R^(A1) is independentlyhalogen, —N(R)₂, —OR, or C₁₋₄ alkyl optionally substituted with one ormore halogen.

In certain embodiments, one R^(A1) is —F, and the other R^(A1) isindependently halogen, —CN, —C(O)N(R)₂, —N(R)₂, —OR, —C(O)R, —N₃, anoptionally substituted 5- or 6-membered heterocyclyl or heteroarylhaving one or two heteroatoms independently selected from nitrogen,oxygen, or sulfur, or C₁₋₄ alkyl optionally substituted with one or morehalogen. In certain embodiments, one R^(A1) is —F, and the other R^(A1)is independently halogen, —CN, —C(O)N(R)₂, —N(R)₂, —OR, —C(O)R, —N₃, a5- or 6-membered heterocyclyl or heteroaryl having one or twoheteroatoms independently selected from nitrogen, oxygen, or sulfur, orC₁₋₄ alkyl optionally substituted with one or more halogen. In certainembodiments, one R^(A1) is —F, and the other R^(A1) is independentlyhalogen, —CN, —C(O)N(R)₂, —N(R)₂, —OR, —C(O)R, —N₃, or C₁₋₄ alkyloptionally substituted with one or more halogen. In certain embodiments,one R^(A1) is —F, and the other R^(A1) is independently halogen, —N(R)₂,—OR, or C₁₋₄ alkyl optionally substituted with one or more halogen. Insome embodiments, Ring A is

In some embodiments, Ring A is

In certain embodiments, one R^(A1) is R^(A2), and the other R^(A1) isindependently halogen, —CN, —C(O)N(R)₂, —N(R)₂, —OR, —C(O)R, —N₃, anoptionally substituted 5- or 6-membered heterocyclyl or heteroarylhaving one or two heteroatoms independently selected from nitrogen,oxygen, or sulfur, or C₁₋₄ alkyl optionally substituted with one or morehalogen. In certain embodiments, one R^(A1) is R^(A2), and the otherR^(A1) is halogen, —CN, —C(O)N(R)₂, —N(R)₂, —OR, —C(O)R, —N₃, a 5- or6-membered heterocyclyl or heteroaryl having one or two heteroatomsindependently selected from nitrogen, oxygen, or sulfur, orindependently C₁₋₄ alkyl optionally substituted with one or morehalogen. In certain embodiments, one R^(A1) is R^(A2), and the otherR^(A1) is independently halogen, —CN, —C(O)N(R)₂, —N(R)₂, —OR, —C(O)R,—N₃, or C₁₋₄ alkyl optionally substituted with one or more halogen. Incertain embodiments, one R^(A1) is R^(A2), and the other R^(A1) isindependently halogen, —N(R)₂, —OR, or C₁₋₄ alkyl optionally substitutedwith one or more halogen. In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, R^(A1) is C₁₋₄ alkyl optionally substituted withone or more halogen. In some embodiments, Ring A is

wherein R^(A1) is C₁₋₄ alkyl optionally substituted with one or morehalogen. In some embodiments, Ring A is

wherein R^(A1) is C₁₋₄ alkyl optionally substituted with one or morehalogen. In some embodiments, Ring A is

wherein R^(A1) is C₁₋₄ alkyl optionally substituted with one or morehalogen. In some embodiments, R^(A1) is C₁₋₄ alkyl. In some embodiments,R^(A1) is C₁₋₄ alkyl substituted with one or more halogen. In someembodiments, R^(A1) is C₁₋₄ alkyl substituted with one or more —F. Insome embodiments, R^(A1) is —CF₃. In some embodiments, Ring A is

In some embodiments, R² is

In some embodiments, R^(A1) is halogen. In some embodiments, Ring A is

wherein R^(A1) is halogen. In some embodiments, Ring A is

wherein R^(A1) is halogen. In some embodiments, Ring A is

wherein R^(A1) is halogen. In some embodiments, Ring A is

wherein R^(A1) is halogen. In some embodiments, Ring A is

wherein R^(A1) is halogen. In some embodiments, R^(A1) is —F. In someembodiments, R^(A1) is —Cl. In some embodiments, R^(A1) is —Br. In someembodiments, R^(A1) is —I. In some embodiments, one R^(A1) is —F, andeach of the other R^(A1) groups is independently selected from —F, —Cl,—Br or —I. In some embodiments, Ring A is F

In some embodiments, R² is

In some embodiments, Ring A is

in some embodiments, R² is

In some embodiments, Ring A is

In some embodiments, R² is

In some embodiments, Ring A is

In some embodiments, R² is

In some embodiments, Ring A is

In some embodiments, R² is

In some embodiments, R^(A1) is —CN. In some embodiments, R^(A1) is—C(O)N(R)₂.

In some embodiments, R^(A1) is —N(R)₂. In some embodiments, R^(A1) is—N(R)₂, wherein each R is independently C₁₋₄ alkyl optionallysubstituted with one or more halogen. In some embodiments, R^(A1) is—N(R)₂, wherein each R is independently C₁₋₄ alkyl. In some embodiments,Ring A is

In some embodiments, Ring A is

wherein each R is independently C₁₋₄ alkyl optionally substituted withone or more halogen. In some embodiments, Ring A is

wherein each R is independently C₁₋₄ alkyl. In some embodiments, Ring Ais

In some embodiments, Ring A is

wherein R^(A1) is —N(R)₂. In some embodiments, Ring A is

wherein R^(A1) is —N(R)₂. In some embodiments, Ring A is

wherein R^(A1) is —N(R)₂. In some embodiments, R^(A1) is —NH₂. In someembodiments, Ring A is

In some embodiments, R² is

In some embodiments, R^(A1) is —N(CH₃)₂. In some embodiments, Ring A is

In some embodiments, R² is

In some embodiments, R^(A1) is —OR. In some embodiments, Ring A is

In some embodiments, Ring A is

wherein R^(A1) is —OR. In some embodiments, Ring A is

wherein R^(A1) is —OR. In some embodiments, Ring A is

wherein R^(A1) is —OR. In some embodiments, Ring A is

wherein R^(A1) is —OR. In some embodiments, Ring A is

wherein R^(A) is —OR. In some embodiments, Ring A is

wherein R^(A1) is —OR. In some embodiments, R^(A1) is —OH. In someembodiments, Ring A is

In some embodiments, R² is

In some embodiments, R^(A1) is —OR, wherein R is C₁₋₄ alkyl optionallysubstituted with one or more halogen. In some embodiments, R^(A1) is—OR, wherein R is C₁₋₄ alkyl. In some embodiments, R^(A1) is —OR,wherein R is methyl. In some embodiments, R^(A1) is —OMe. In someembodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, R² is

In some embodiments, Ring A is

In some embodiments, R² is

In some embodiments, Ring A is

In some embodiments, R² is

In some embodiments, Ring A is

In some embodiments, R² is

In some embodiments, n is 1-4. In some embodiments, n is 1-2. In someembodiments, n is 1-3. In some embodiments, n is 2-3. In someembodiments, n is 2-4. In some embodiments, n is 1. In some embodiments,n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

In some embodiments, Ring A is

wherein R^(A2) is —F, —Cl, —Br, —I, —CN, —C(O)N(R)₂, —N(R)₂, —OR,—C(O)R, —N₃, an optionally substituted 5- or 6-membered heterocyclyl orheteroaryl having one or two heteroatoms independently selected fromnitrogen, oxygen or sulfur, or C₁₋₄ alkyl optionally substituted withone or more halogen. In some embodiments, Ring A is

wherein R^(A2) is —Cl, —Br, —I, —CN, —C(O)N(R)₂, —N(R)₂, —OR, —C(O)R,—N₃, a 5- or 6-membered heterocyclyl or heteroaryl having one or twoheteroatoms independently selected from nitrogen, oxygen or sulfur, orC₁₋₄ alkyl optionally substituted with one or more halogen. In someembodiments, R^(A2) is —Cl, —I, —CN, —C(O)N(R)₂, —N(R)₂, —OR, —C(O)R,—N₃, an optionally substituted 5- or 6-membered heterocyclyl orheteroaryl having one or two heteroatoms independently selected fromnitrogen, oxygen or sulfur, or C₁₋₄ alkyl optionally substituted withone or more halogen. In some embodiments, R^(A2) is, —I, —CN,—C(O)N(R)₂, —N(R)₂, —OR, —C(O)R, —N₃, a 5- or 6-membered heterocyclyl orheteroaryl having one or two heteroatoms independently selected fromnitrogen, oxygen or sulfur, or C₁₋₄ alkyl optionally substituted withone or more halogen.

In some embodiments, R^(A2) is —Cl. In some embodiments, Ring A is

In some embodiments, R² is

In some embodiments, R^(A2) is —I. In some embodiments, Ring A is

In some embodiments, R² is

In some embodiments, R^(A2) is —F. In some embodiments, R² is

In some embodiments, R^(A2) is —Br. In some embodiments, R² is

In some embodiments, R^(A2) is —CN. In some embodiments, Ring A is

In some embodiments, R² is

In some embodiments, R^(A2) is —N(R)₂. In some embodiments, R^(A2) is—N(R)₂, wherein each R is hydrogen. In some embodiments, Ring A is

In some embodiments, R² is

In some embodiments, R^(A2) is —N(R)₂, wherein each R is independentlyC₁₋₄ alkyl. In some embodiments, Ring A is

In some embodiments, R² is N

In some embodiments, R^(A2) is —N(R)₂, wherein one R is hydrogen, andthe other R is C₁₋₄ alkyl. In some embodiments, R^(A2) is —N(R)₂,wherein one R is hydrogen, and the other R is C₁₋₄ alkyl. cycloalkyl. Insome embodiments, Ring A is

in some embodiments, R² is

In some embodiments, R^(A2) is —C(O)N(R)₂. In some embodiments, R^(A2)is —C(O)N(R)₂, wherein each R is hydrogen. In some embodiments, Ring Ais

In some embodiments, R² is

In some embodiments, R^(A2) is —OR. In some embodiments, R^(A2) is —OR,wherein each R is hydrogen. In some embodiments, Ring A is

In some embodiments, R² is

In some embodiments, R^(A2) is —OR, wherein R is C₁₋₄ alkyl optionallysubstituted with one or more halogen. In some embodiments, R^(A2) is—OR, wherein R C₁₋₄ alkyl. In some embodiments, Ring A is

In some embodiments, R² is

In some embodiments, R^(A2) is —OR, wherein R C₁₋₄ alkyl substitutedwith one or more halogen. In some embodiments, R^(A2) is —OR, wherein RC₁₋₄ alkyl substituted with one or more —F. In some embodiments, R is—CF₃. In some embodiments, Ring A is

In some embodiments, R² is

In some embodiments, R is —CHF₂. In some embodiments, Ring A is

In some embodiments, R² is

In some embodiments, R^(A2) is —C(O)R. In some embodiments, R^(A2) is—C(O)R, wherein each R is C₁₋₄ alkyl. In some embodiments, R is methyl.In some embodiments, Ring A is

In some embodiments, R² is

In some embodiments, R^(A2) is —N₃. In some embodiments, Ring A is

In some embodiments, R² is

In some embodiments, R^(A2) is C₁₋₄ alkyl optionally substituted withone or more halogen. In some embodiments, R^(A2) is C₁₋₄ alkyl. In someembodiments, R^(A2) is C₁₋₄ alkyl substituted with one or more halogen.In some embodiments, R^(A2) is C₁₋₄ alkyl substituted with one or more—F. In some embodiments, R^(A2) is —CF₃. In some embodiments, Ring A is

In some embodiments, R² is

In some embodiments, R^(A2) is C₁₋₄ alkyl with no branching at thebenzylic position.

In some embodiments, R^(A2) is an optionally substituted 5- or6-membered heterocyclyl or heteroaryl having one or two heteroatomsindependently selected from nitrogen, oxygen or sulfur. In someembodiments, R^(A2) is 5- or 6-membered heterocyclyl or heteroarylhaving one or two heteroatoms independently selected from nitrogen,oxygen or sulfur. In some embodiments, R^(A2) is an optionallysubstituted 5- or 6-membered heterocyclyl or heteroaryl having one ortwo nitrogen atoms. In some embodiments, R^(A2) is 5- or 6-memberedheterocyclyl or heteroaryl having one or two nitrogen atoms. In someembodiments, R^(A2) is an optionally substituted 5-membered heterocyclylor heteroaryl having one or two heteroatoms independently selected fromnitrogen, oxygen or sulfur. In some embodiments, R^(A2) is 5-memberedheterocyclyl or heteroaryl having one or two heteroatoms independentlyselected from nitrogen, oxygen or sulfur. In some embodiments, R^(A2) isan optionally substituted 5-membered heterocyclyl or heteroaryl havingone or two nitrogen atoms. In some embodiments, R^(A2) is 5-memberedheterocyclyl or heteroaryl having one or two nitrogen atoms. In someembodiments, R^(A2) is an optionally substituted 5-membered heterocyclylhaving one or two nitrogen atoms. In some embodiments, R^(A2) is5-membered heterocyclyl having one or two nitrogen atoms. In someembodiments, R^(A2) is an optionally substituted 5-membered heterocyclylhaving one nitrogen atom. In some embodiments, R^(A2) is 5-memberedheterocyclyl having one nitrogen atom. In some embodiments, R^(A2) isoptionally substituted 5-membered heterocyclyl having two nitrogenatoms. In some embodiments, R^(A2) is 5-membered heterocyclyl having twonitrogen atoms. In some embodiments, R^(A2) is optionally substituted5-membered heteroaryl having one or two nitrogen atoms. In someembodiments, R^(A2) is 5-membered heteroaryl having one or two nitrogenatoms. In some embodiments, R^(A2) is optionally substituted 5-memberedheteroaryl having one nitrogen atom. In some embodiments, R^(A2) is5-membered heteroaryl having one nitrogen atom. In some embodiments,R^(A2) is optionally substituted 5-membered heteroaryl having twonitrogen atoms. In some embodiments, R^(A2) is 5-membered heteroarylhaving two nitrogen atoms. In some embodiments, R^(A2) is

In some embodiments, Ring A is

In some embodiments, R² is

In some embodiments, R^(A2) is

In some embodiments, Ring A is

In some embodiments, R² is

In some embodiments, R^(A2) is —I, —CN, —NH₂, —N(CH₃)₂,—NH(cyclopropyl), —C(O)NH₂, —OH, —OMe, —OCF₃, —OCHF₂, —C(O)Me, —N₃,—CF₃,

In some embodiments, Ring A is

In some embodiments, R^(A3) is —H or —F. In some embodiments, R^(A3) is—H. In some embodiments, Ring A is

In some embodiments, R^(A3) is —F. In some embodiments, Ring A is

In some embodiments, R^(A4) is —F or —OR. In some embodiments, R^(A4) is—F. In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, R² is

In some embodiments, Ring A is

In some embodiments, R² is

In some embodiments, R^(A4) is —OR. In some embodiments, Ring A is

In some embodiments, R^(A4) is —OR, wherein R is C₁₋₄ alkyl. In someembodiments, R^(A4) is —OMe. In some embodiments, Ring A is

In some embodiments, R² is

In some embodiments, Ring A is pyridinyl optionally substituted withR^(A5). In some embodiments, Ring A is pyridinyl. In some embodiments,Ring A is pyridinyl substituted with R^(A5).

In some embodiments, R^(A5) is —OR or —N(R)₂. In some embodiments,R^(A5) is —OR. In some embodiments, Ring A is pyridinyl substituted withR^(A5), wherein R^(A5) is —OR. In some embodiments, R^(A5) is —OR,wherein R is C₁₋₄ alkyl. In some embodiments, Ring A is pyridinylsubstituted with R^(A5), wherein R^(A5) is —OR, wherein R is C₁₋₄ alkyl.In some embodiments, R^(A5) is —OMe. In some embodiments, Ring A ispyridinyl substituted with —OMe. In some embodiments, Ring A is

In some embodiments, R² is

In some embodiments, Ring A is

In some embodiments, R² is

In some embodiments, Ring A is

In some embodiments, R² is

In some embodiments, Ring A is

In some embodiments, R² is

In some embodiments, R^(A5) is —N(R)₂. In some embodiments, Ring A ispyridinyl substituted with R^(A5), wherein R^(A5) is —N(R)₂. In someembodiments, R^(A5) is —N(R)₂, wherein each R is hydrogen. In someembodiments, Ring A is pyridinyl substituted with R^(A5), wherein R^(A5)is —NH₂. In some embodiments, Ring A is

In some embodiments, R² is

Exemplary Ring A groups are depicted in Table 2, below.

TABLE 2 Exemplary Ring A groups.

In some embodiments, R² is —NH—CH₂-Ring A. In some embodiments, R² is

In some embodiments, R² is

In some embodiments, R² is —O—CH₂CH₂-Ring A.

Exemplary R² groups are depicted in Table 3, below.

TABLE 3 Exemplary R2 groups.

In some embodiments, R³ is —C(O)N(R^(3a))₂, —OR^(3b), —C(O)H, —C(O)OR,or —N(R^(3c))₂. In some embodiments, R³ is —C(O)N(R^(3a))₂. In someembodiments, R³ is —OR^(3b). In some embodiments, R³ is —C(O)H. In someembodiments, R³ is —C(O)OR. In some embodiments, R³ is —N(R^(3c))₂.

In some embodiments, each R^(3a) is independently hydrogen or C₁ alkyloptionally substituted with one or more groups independently selectedfrom halogen or 1-pyrrolidinyl.

In some embodiments, R^(3a) is hydrogen. In some embodiments, eachR^(3a) is hydrogen. In some embodiments, R³ is —C(O)NH₂.

In some embodiments, R^(3a) is C₁ alkyl optionally substituted with oneor more groups independently selected from halogen or 1-pyrrolidinyl. Insome embodiments, R^(3a) is C₁ alkyl optionally substituted with1-pyrrolidinyl. In some embodiments, R^(3a) is methyl. In someembodiments, R^(3a) is

In some embodiments, one R^(3a) is hydrogen, and the other R^(3a) is C₁alkyl optionally substituted with one or more groups independentlyselected from halogen or 1-pyrrolidinyl. In some embodiments, one R^(3a)is hydrogen, and the other R^(3a) is C₁ alkyl optionally substitutedwith 1-pyrrolidinyl. In some embodiments, one R^(3a) is hydrogen, andthe other R^(3a) is methyl. In some embodiments, R³ is —CONH(CH₃). Insome embodiments, one R^(3a) is hydrogen, and the other R^(3a) is

In some embodiments, R³ is

In some embodiments, R^(3b) is hydrogen or C₁₋₄ alkyl optionallysubstituted with one or more groups independently selected from halogen,C₁₋₄ alkyl, C₁₋₄ haloalkyl, oxo, or —N(R)₂. In some embodiments, R^(3b)is hydrogen or C₁₋₄ alkyl.

In some embodiments, R^(3b) is hydrogen. In some embodiments, R³ is —OH.

In some embodiments, R^(3b) is C₁₋₄ alkyl optionally substituted withone or more groups independently selected from halogen, C₁₋₄ alkyl, C₁₋₄haloalkyl, oxo, or —N(R)₂. In some embodiments, R^(3b) is C₁₋₄ alkyl. Insome embodiments, R^(3b) is methyl. In some embodiments, R³ is —OMe. Insome embodiments, R^(3b) is —CH(CH₃)C(O)NH₂. In some embodiments, R³ is—OCH(CH₃)C(O)NH₂.

In some embodiments, R³ is —C(O)H.

In some embodiments, R³ is —C(O)OR, wherein R is C₁₋₄ alkyl. In someembodiments, R is methyl. In some embodiments, R³ is —C(O)OMe.

In some embodiments, each R^(3c) is independently hydrogen or C₁₋₄ alkyloptionally substituted with one or more groups independently selectedfrom halogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, oxo, or —N(R)₂.

In some embodiments, R^(3c) is hydrogen. In some embodiments, eachR^(3c) is hydrogen. In some embodiments, R³ is —NH₂.

In some embodiments, R^(3c) is C₁₋₄ alkyl optionally substituted withone or more groups independently selected from halogen, C₁₋₄ alkyl, C₁₋₄haloalkyl, oxo, or —N(R)₂. In some embodiments, one R^(3c) is hydrogen,and the other R^(3c) is C₁₋₄ alkyl optionally substituted with one ormore groups independently selected from halogen, C₁₋₄ alkyl, C₁₋₄haloalkyl, oxo, or —N(R)₂. In some embodiments, one R^(3c) is hydrogen,and the other R^(3c) is C₁₋₄ alkyl optionally substituted with one ormore groups independently selected from oxo or —N(R)₂. In someembodiments, R³ is —NHC(O)CH₂NH₂.

In some embodiments, R⁴ is R or halogen. In some embodiments, R⁴ is R.In some embodiments, R⁴ is hydrogen. In some embodiments, R⁴ is C₁₋₄alkyl optionally substituted with one or more halogen. In someembodiments, R⁴ is C₁₋₄ alkyl. In some embodiments, R⁴ is methyl. Insome embodiments, R⁴ is C₁₋₄ alkyl substituted with one or more halogen.In some embodiments, R⁴ is —CF₃.

In some embodiments, R⁴ is halogen. In some embodiments, R⁴ is —F. Insome embodiments, R⁴ is —Cl. In some embodiments, R⁴ is —Br. In someembodiments, R⁴ is —I.

In some embodiments, R⁴ is —N(R)₂. In some embodiments, R⁴ is —N(R)₂,wherein each R is hydrogen. In some embodiments, R⁴ is —NH₂.

In some embodiments, R⁵ is hydrogen, methyl or —N(R)₂. In someembodiments, R⁵ is hydrogen. In some embodiments, R⁵ is methyl. In someembodiments, R⁵ is —N(R)₂. In some embodiments, R⁵ is —N(R)₂, whereineach R is hydrogen. In some embodiments, R⁵ is —NH₂.

In some embodiments, each R is independently hydrogen or C₁₋₄ alkyloptionally substituted with one or more halogen. In some embodiments,each R is independently hydrogen or unsubstituted C₁₋₄ alkyl. In someembodiments, each R is independently hydrogen or C₁₋₄ alkyl optionallysubstituted with one or more —F.

In some embodiments, R is hydrogen. In some embodiments, R is C₁₋₄ alkyloptionally substituted with one or more halogen. In some embodiments, Ris hydrogen or C₁₋₄ alkyl optionally substituted with one or more —F. Insome embodiments, R is hydrogen or C₁₋₄ alkyl. In some embodiments, R isC₁₋₄ alkyl. In some embodiments, R is methyl. In some embodiments, R ishydrogen or C₁₋₄ alkyl substituted with one or more halogen. In someembodiments, R is hydrogen or C₁₋₄ alkyl substituted with one or more—F. In some embodiments, R is —CF₃. In some embodiments, R is —CHF₂.

In some embodiments, the right hand side of formula I,

is

In some embodiments,

is

In some embodiments,

is

In some embodiments,

is

In some embodiments,

is

In some embodiments,

is

In some embodiments,

is

In some embodiments,

is

In some embodiments,

is not

Exemplary

moieties are depicted in Table 4, below.

TABLE 4

In some embodiments, a compound of formula I has the structure offormula I-a:

or a pharmaceutically acceptable salt thereof, wherein each variable isindependently as described in classes and subclasses herein, both singlyand in combination. In some embodiments, R^(1a) is

or straight chain C₁₋₆ aliphatic optionally substituted with one or moregroups independently selected from —OH, cyclopropyl, —C≡CH or 5-memberedheteroaryl having 1-2 heteroatoms independently selected from nitrogen,oxygen or sulfur.

In some embodiments, a compound of formula I has the structure offormula I-a-1:

or a pharmaceutically acceptable salt thereof, wherein each variable isindependently as described in classes and subclasses herein, both singlyand in combination. In some embodiments, R^(1a) is

or straight chain C₁₋₆ aliphatic optionally substituted with one or moregroups independently selected from —OH, cyclopropyl, —C≡CH, or5-membered heteroaryl having 1-2 heteroatoms independently selected fromnitrogen, oxygen or sulfur.

In some embodiments, a compound of formula I has the structure offormula I-a-2:

or a pharmaceutically acceptable salt thereof, wherein each variable isindependently as described in classes and subclasses herein, both singlyand in combination. In some embodiments, R^(1a) is

or straight chain C₁₋₆ aliphatic optionally substituted with one or moregroups independently selected from —OH, cyclopropyl, —C≡CH, or5-membered heteroaryl having 1-2 heteroatoms independently selected fromnitrogen, oxygen or sulfur.

In some embodiments, a compound of formula I has the structure offormula I-b:

or a pharmaceutically acceptable salt thereof, wherein each variable isindependently as described in classes and subclasses herein, both singlyand in combination.

In some embodiments, a compound of formula I has the structure offormula I-c:

or a pharmaceutically acceptable salt thereof, wherein each variable isindependently as described in classes and subclasses herein, both singlyand in combination. In some embodiments, each of R^(1c) and R^(1d) ismethyl. In some embodiments, R^(1c) is hydrogen and R^(1d) is methyl.

In some embodiments, a compound of formula I has the structure offormula I-c-1:

or a pharmaceutically acceptable salt thereof, wherein each variable isindependently as described in classes and subclasses herein, both singlyand in combination. In some embodiments, each of R^(1c) and R^(1d) ismethyl. In some embodiments, R^(1c) is hydrogen and R^(1d) is methyl.

In some embodiments, a compound of formula I has the structure offormula I-d:

or a pharmaceutically acceptable salt thereof, wherein each variable isindependently as described in classes and subclasses herein, both singlyand in combination. In some embodiments, R^(A2) is —OMe. In someembodiments, R^(A2) is —N(R)₂, wherein each R is independently C₁₋₄alkyl. In some embodiments, R^(A2) is —N(CH₃)₂. In some embodiments,R^(A2) is —Cl, R^(A1) is —F, and n is 1.

In some embodiments, a compound of formula I has the structure offormula I-e:

or a pharmaceutically acceptable salt thereof, wherein each variable isindependently as described in classes and subclasses herein, both singlyand in combination.

In some embodiments, a compound of formula I has the structure offormula I-e-1:

or a pharmaceutically acceptable salt thereof, wherein each variable isindependently as described in classes and subclasses herein, both singlyand in combination.

In some embodiments, a compound of formula I has the structure offormula I-f:

or a pharmaceutically acceptable salt thereof, wherein each variable isindependently as described in classes and subclasses herein, both singlyand in combination. In some embodiments, R^(A2) is —OMe. In someembodiments, R^(A2) is —N(R)₂, wherein each R is independently C₁₋₄alkyl. In some embodiments, R^(A2) is —N(CH₃)₂. In some embodiments,R^(A2) is —Cl.

In some embodiments, a compound of formula I has the structure offormula I-g:

or a pharmaceutically acceptable salt thereof, wherein each variable isindependently as described in classes and subclasses herein, both singlyand in combination.

Exemplary compounds of formula I are depicted in Table 5, below.

TABLE 5 Exemplary componds of formula I.

10

11

32

37

45

49

58

62

65

66

70

73

74

77

78

79

80

83

84

92

100a

100b

100c

100e

100f

100g

100h

100i

100j

100m

100q

100s

100t

100u

100w

100x

101

102

108

109

110

111

112

113

114

115

116

117

118

121

122

123

124

125

126

127

131

132

133

134

135

136

137

138

139

141

146c

146e

151

152

153

154

155

156

157

158

185d

185e

190a

190b

190e

190j

190k

190m

190n

190o

190p

190q

190r

190t

190u

190v

198

205

206

207

208

212

214

218

225

226

228

229

321

323

326

329

336

339

348

354

357

360

363

365

367

369

375

376

379

In certain embodiments, the present invention provides a compound offormula II or a pharmaceutically acceptable salt thereof.

In some embodiments, Y is —S—. In some embodiments, Y is —O—. In someembodiments, a compound of formula II is

or a pharmaceutically acceptable salt thereof. In some embodiments, Y is—CR₂—. In some embodiments, Y is —CH₂—. In some embodiments, a compoundof formula II is

or a pharmaceutically acceptable salt thereof.

In some embodiments, Ring B is

In some embodiments, Ring B is

In some embodiments, Ring B is

In some embodiments, Ring B is

In some embodiments, Ring B is

In some embodiments, Ring B is

In some embodiments, Ring B is

In some embodiments, Ring B is

In some embodiments, Ring B is

In some embodiments, Ring B is

In some embodiments, Ring B is thienyl optionally substituted with—C(O)R. In some embodiments, Ring B is thienyl optionally substitutedwith —C(O)Me. In some embodiments, Ring B is

In some embodiments, Ring B is furanyl optionally substituted with—C(O)R. In some embodiments, Ring B is furanyl optionally substitutedwith —C(O)H. In some embodiments, Ring B is

In some embodiments, a compound of formula II has the structure offormula II-a:

or a pharmaceutically acceptable salt thereof, wherein each variable isindependently as described in classes and subclasses herein, both singlyand in combination.

Exemplary compounds of formula II are depicted in Table 6, below.

Uses

In some embodiments, the compounds of formulae I and/or II are useful inmedicine. In some embodiments, the present invention provides a methodof treating a subject suffering from or susceptible to a disease,disorder, or condition responsive to Hsp70 inhibition, the methodcomprising administering to the subject a therapeutically effectiveamount of a compound as described herein. In some embodiments, adisease, disorder, or condition is a proliferative disease, disorder, orcondition. In some embodiments, a disease, disorder, or condition iscancer.

In certain embodiments, provided compounds have been found to possessanti-proliferative activity and are therefore believed to be of use inthe treatment of proliferative disorders such as cancers and otherdisorders associated with uncontrolled cellular proliferation. Asdefined herein, an anti-proliferative effect within the scope of thepresent subject matter may be demonstrated, by way of nonlimitingexample, by the ability to inhibit cell proliferation specific genetargets in vitro or in vivo, or inhibit cell proliferation in an invitro whole cell assay, in an in vivo animal model, or in human clinicaladministration.

Provided compounds may be used in vitro or in vivo. In some embodiments,provided compounds may be particularly useful in the treatment ofneoplasms or other proliferative diseases in vivo. However, providedcompounds described above may also be used in vitro for research orclinical purposes (e.g., determining the susceptibility of a patient'sdisease to a provided compound, researching the mechanism of action,elucidating a cellular pathway or process). In certain embodiments, theneoplasm is a benign neoplasm. In other embodiments, the neoplasm is amalignant neoplasm.

In certain embodiments, the malignancy is a hematological malignancy.Hematological malignancies are types of cancers that affect the blood,bone marrow, and/or lymph nodes. Examples of hematological malignanciesthat may be treated using provided compounds include, but are notlimited to, acute lymphoblastic leukemia (ALL), acute myelogenousleukemia (AML), chronic myelogenous leukemia (CML), chronic lymphocyticleukemia (CLL), hairy cell leukemia, Hodgkin's lymphoma, non-Hodgkin'slymphoma, cutaneous T-cell lymphoma (CTCL), peripheral T-cell lymphoma(PTCL), Mantle cell lymphoma, B-cell lymphoma, acute lymphoblastic Tcell leukemia (T-ALL), acute promyelocytic leukemia, and multiplemyeloma. In certain embodiments, provided compounds are used to treatmultiple myeloma, glioblastoma, epithelial carcinoma, cervicaladenocarcinoma, or well-differentiated liposarcoma. In certainparticular embodiments, the cancer is relapsed and/or refractorymultiple myeloma. In other embodiments, provided compounds are used totreat chromic lymphocytic leukemia (CLL). In certain embodiments,provided compounds are used to treat acute lymphoblastic leukemia (ALL).In certain embodiments, provided compounds are used to treat acutemyelogenous leukemia (AML). In certain embodiments, the cancer is achronic myeloid leukemia (CML). In certain embodiments, the cancer iscutaneous T-cell lymphoma. In other embodiments, the cancer isperipheral T-cell lymphoma. provided compounds may also be used totreated a refractory or relapsed malignancy. In certain embodiments, thecancer is a refractory and/or relapsed hematological malignancy. Incertain embodiments, the cancer is multidrug resistant. For example, thecancer may be resistant to a particular chemotherapeutic agent.

Other cancers besides hematological malignancies may also be treatedusing provided compounds. In certain embodiments, the cancer is a solidtumor. Exemplary cancers that may be treated using provided compoundsinclude colon cancer, lung cancer, bone cancer, pancreatic cancer,stomach cancer, esophageal cancer, skin cancer, brain cancer, livercancer, ovarian cancer, cervical cancer, uterine cancer, testicularcancer, prostate cancer, bladder cancer, kidney cancer, neuroendocrinecancer, breast cancer, gastric cancer, eye cancer, gallbladder cancer,laryngeal cancer, oral cancer, penile cancer, glandular tumors, rectalcancer, small intestine cancer, sarcoma, carcinoma, melanoma, urethralcancer, vaginal cancer, to name but a few.

In some embodiments, provided compounds may also be used to treat and/orkill cells in vitro. In certain embodiments, a cytotoxic concentrationof a provided compound is contacted with the cells in order to killthem. In other embodiments, a sublethal concentration of a providedcompound is used to treat the cells. In certain embodiments, theconcentration of a provided compound ranges from 0.01 nM to 100 nM. Incertain embodiments, the concentration of a provided compound rangesfrom 0.1 nM to 50 nM. In certain embodiments, the concentration of aprovided compound ranges from 1 nM to 10 nM. In certain embodiments, theconcentration of a provided compound ranges from 1 nM to 10 nM, moreparticularly 1 nM to 5 nM.

Any type of cell may be tested or killed with provided compound. Thecells may be at any stage of differentiation or development. In certainembodiments, the cells are animal cells. In certain embodiments, thecells are vertebrate cells. In certain embodiments, the cells aremammalian cells. In certain embodiments, the cells are human cells. Thecells may be derived from a male or female human in any stage ofdevelopment. In certain embodiments, the cells are primate cells. Inother embodiments, the cells are derived from a rodent (e.g., mouse,rat, guinea pig, hamster, gerbil). In certain embodiments, the cells arederived from a domesticated animal such as a dog, cat, cow, goat, pig,etc. The cells may also be derived from a genetically engineered animalor plant, such as a transgenic mouse.

The cells used may be wild type or mutant cells. The cells may begenetically engineered. In certain embodiments, the cells are normalcells. In certain embodiments, the cells are hematological cells. Incertain embodiments, the cells are white blood cells. In certainparticular embodiments, the cells are precursors of white blood cells(e.g., stem cells, progenitor cells, blast cells). In certainembodiments, the cells are neoplastic cells. In certain embodiments, thecells are cancer cells. In certain embodiments, the cells are derivedfrom a hematological malignancy. In other embodiments, the cells arederived from a solid tumor. For example, the cells may be derived from apatient's tumor (e.g., from a biopsy or surgical excision). In certainembodiments, the cells are derived from a blood sample from the subjector from a bone marrow biopsy. In certain embodiments, the cells arederived from a lymph node biopsy. Such testing for cytotoxicity may beuseful in determining whether a patient's disease will respond to aparticular therapy. Such testing may also be useful in determining thedosage needed to treat the malignancy. This testing of thesusceptibility of a patient's cancer to provided compound would preventthe unnecessary administration of drugs with no effect to the patient.The testing may also allow the use of lower dose of an inventivecompound if the patient's cancer is particularly susceptible to thecompound.

In some embodiments, the cells are derived from cancer cells lines. Incertain embodiments, the cells are from hematological malignancies suchas those discussed herein. Human leukemia cell lines include U937,HL-60, HL-60/RV+ (a P-glycoprotein over-expressing multidrug resistantHL-60 variant which was selected by continuous exposure to the vincaalkaloid vincristine), THP-1, Raji, CCRF-CEM, ALL3 (acute lymphoblasticleukemia isolated from a patient treated at Memorial Sloan KetteringCancer Center and characterized as Philadelphia chromosome positive),and Jurkat. Exemplary CLL cell lines include JVM-3 and MEC-2. Exemplarymyeloma cells lines include MM1.S, MM1.R (dexamethasone-resistant),RPMI8226, NCI-H929, and U266. Exemplary lymphoma cell lines includeNCEB1 (Mantle cell lymphoma), JEKO (B cell lymphoma), Karpas, SUDH-6,SUDH-16, L428, KMH2, and Granta mantle lymphoma cell line. In certainembodiments, the cells are AML cells or multiple myeloma (CD138⁺) cells.In certain embodiments, the cells are hematopoietic stem or progenitorcells. For example, in certain embodiments, the cells are hematopoieticprogenitor cells such as CD34⁺ bone marrow cells. In certainembodiments, the cells are MOLT-3 (acute lymphoblastic T-cell), SKNLP(neuroblastoma), PC9 (adenocarcinoma), H1650 (adeocarcinoma), H1975(adeocarcinoma), H2030 (adeocarcinoma), H3255 (adeocarcinoma), TC71(Ewing's sarcoma), HTP-15 (glioblastoma), A431 (epithelial carcinoma),HeLa (cervical adenocarcinoma), or WD0082 (well-differentiatedliposarcoma) cells. In some embodiments, the cells are HL-60/RV+ cells.In certain embodiments, the cell lines are resistant to a particularchemotherapeutic agent.

In some embodiments, a cancer is refractory to treatment with Hsp90inhibitors. Cancers resistant to Hsp90 inhibitors can be particularlydifficult to treat. It is surprisingly found that a provided compoundactivates caspase, induced cell death and/or inhibited cell growth whenadministered to cells resistant to Hsp90 inhibitors. In someembodiments, the present invention provides a method for activatingcaspase in cells resistant to Hsp90 inhibitors, comprising administeringto the cells a provided compound or a composition. In some embodiments,the present invention provides a method for inducing cell death in cellsresistant to Hsp90 inhibitors, comprising administering to the cells aprovided compound or a composition. In some embodiments, the presentinvention provides a method for inducing apoptosis in cells resistant toHsp90 inhibitors, comprising administering to the cells a providedcompound or a composition. In some embodiments, the present inventionprovides a method for inhibiting cell growth in cells resistant to Hsp90inhibitors, comprising administering to the cells a provided compound ora composition.

In certain embodiments, provided compounds are useful in treating asubject in clinical remission, where the subject has been treated bysurgery or has limited unresected disease. In some embodiments, asubject has been previously treated by Hsp90 inhibitor.

Pharmaceutical Compositions

In another aspect, the present invention provides pharmaceuticalcompositions comprising a compound of formulae I or II in combinationwith a pharmaceutically acceptable excipient (e.g., carrier).

The pharmaceutical compositions include optical isomers, diastereomers,or pharmaceutically acceptable salts of the compounds disclosed herein.A provided compound included in the pharmaceutical composition may becovalently attached to a carrier moiety, as described above.Alternatively, a provided compound included in the pharmaceuticalcomposition is not covalently linked to a carrier moiety.

A “pharmaceutically acceptable carrier,” as used herein refers topharmaceutical excipients, for example, pharmaceutically,physiologically, acceptable organic or inorganic carrier substancessuitable for enteral or parenteral application that do not deleteriouslyreact with the active agent. Suitable pharmaceutically acceptablecarriers include water, salt solutions (such as Ringer's solution),alcohols, oils, gelatins, and carbohydrates such as lactose, amylose orstarch, fatty acid esters, hydroxymethycellulose, and polyvinylpyrrolidine. Such preparations can be sterilized and, if desired, mixedwith auxiliary agents such as lubricants, preservatives, stabilizers,wetting agents, emulsifiers, salts for influencing osmotic pressure,buffers, coloring, and/or aromatic substances and the like that do notdeleteriously react with the compounds of the invention.

The compounds of the invention can be administered alone or can beco-administered to the subject. Co-administration is meant to includesimultaneous or sequential administration of the compounds individuallyor in combination (more than one compound). The preparations can also becombined, when desired, with other active substances (e.g. to reducemetabolic degradation).

Compounds of the present invention can be prepared and administered in awide variety of oral, parenteral, and topical dosage forms. Thus, thecompounds of the present invention can be administered by injection(e.g. intravenously, intramuscularly, intracutaneously, subcutaneously,intraduodenally, or intraperitoneally). Also, the compounds describedherein can be administered by inhalation, for example, intranasally.Additionally, the compounds of the present invention can be administeredtransdermally. It is also envisioned that multiple routes ofadministration (e.g., intramuscular, oral, transdermal) can be used toadminister the compounds of the invention.

For preparing pharmaceutical compositions from the compounds of thepresent invention, pharmaceutically acceptable carriers can be eithersolid or liquid. Solid form preparations include powders, tablets,pills, capsules, cachets, suppositories, and dispersible granules. Asolid carrier can be one or more substance that may also act asdiluents, flavoring agents, binders, preservatives, tabletdisintegrating agents, or an encapsulating material.

In powders, the carrier is a finely divided solid in a mixture with thefinely divided active component. In tablets, the active component ismixed with the carrier having the necessary binding properties insuitable proportions and compacted in the shape and size desired.

The powders and tablets preferably contain from 5% to 70% of the activecompound. Suitable carriers include magnesium carbonate, magnesiumstearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin,tragacanth, methylcellulose, sodium carboxymethylcellulose, a lowmelting wax, cocoa butter, and the like. The term “preparation” isintended to include the formulation of the active compound withencapsulating material as a carrier providing a capsule in which theactive component with or without other carriers, is surrounded by acarrier, which is thus in association with it. Similarly, cachets andlozenges are included. Tablets, powders, capsules, pills, cachets, andlozenges can be used as solid dosage forms suitable for oraladministration.

For preparing suppositories, a low melting wax, such as a mixture offatty acid glycerides or cocoa butter, is first melted and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogeneous mixture is then poured into convenient sized molds, allowedto cool, and thereby to solidify.

Liquid form preparations include solutions, suspensions, and emulsions,for example, water or water/propylene glycol solutions. For parenteralinjection, liquid preparations can be formulated in solution in aqueouspolyethylene glycol solution.

When parenteral application is needed or desired, particularly suitableadmixtures for the compounds of the invention are injectable, sterilesolutions, preferably oily or aqueous solutions, as well as suspensions,emulsions, or implants, including suppositories. In particular, carriersfor parenteral administration include aqueous solutions of dextrose,saline, pure water, ethanol, glycerol, propylene glycol, peanut oil,sesame oil, polyoxyethylene-block polymers, and the like. Ampoules areconvenient unit dosages. The compounds of the invention can also beincorporated into liposomes or administered via transdermal pumps orpatches. Pharmaceutical admixtures suitable for use in the presentinvention include those described, for example, in PharmaceuticalSciences (17th Ed., Mack Pub. Co., Easton, Pa.) and WO 96/05309, theteachings of both of which are hereby incorporated by reference.

Aqueous solutions suitable for oral use can be prepared by dissolvingthe active component in water and adding suitable colorants, flavors,stabilizers, and thickening agents as desired. Aqueous suspensionssuitable for oral use can be made by dispersing the finely dividedactive component in water with viscous material, such as natural orsynthetic gums, resins, methylcellulose, sodium carboxymethylcellulose,and other well-known suspending agents.

Also included are solid form preparations that are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

The pharmaceutical preparation is preferably in unit dosage form. Insuch form the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

The quantity of active component in a unit dose preparation may bevaried or adjusted from 0.1 mg to 10000 mg, more typically 1.0 mg to1000 mg, most typically 10 mg to 500 mg, according to the particularapplication and the potency of the active component. The compositioncan, if desired, also contain other compatible therapeutic agents.

Some compounds may have limited solubility in water and therefore mayrequire a surfactant or other appropriate co-solvent in the composition.Such co-solvents include: Polysorbate 20, 60, and 80; Pluronic F-68,F-84, and P-103; cyclodextrin; and polyoxyl 35 castor oil. Suchco-solvents are typically employed at a level between about 0.01% andabout 2% by weight.

Viscosity greater than that of simple aqueous solutions may be desirableto decrease variability in dispensing the formulations, to decreasephysical separation of components of a suspension or emulsion offormulation, and/or otherwise to improve the formulation. Such viscositybuilding agents include, for example, polyvinyl alcohol, polyvinylpyrrolidone, methyl cellulose, hydroxy propyl methylcellulose,hydroxyethyl cellulose, carboxymethyl cellulose, hydroxy propylcellulose, chondroitin sulfate and salts thereof, hyaluronic acid andsalts thereof, and combinations of the foregoing. Such agents aretypically employed at a level between about 0.01% and about 2% byweight.

The compositions of the present invention may additionally includecomponents to provide sustained release and/or comfort. Such componentsinclude high molecular weight, anionic mucomimetic polymers, gellingpolysaccharides, and finely-divided drug carrier substrates. Thesecomponents are discussed in greater detail in U.S. Pat. Nos. 4,911,920;5,403,841; 5,212,162; and 4,861,760. The entire contents of thesepatents are incorporated herein by reference in their entirety.

Effective Dosages

Pharmaceutical compositions provided by the present invention includecompositions wherein the active ingredient is contained in atherapeutically effective amount, i.e., in an amount effective toachieve its intended purpose. The actual amount effective for aparticular application will depend, inter alia, on the condition beingtreated. For example, when administered in methods to treat cancer, suchcompositions will contain an amount of active ingredient effective toachieve the desired result (e.g. decreasing the number of cancer cellsin a subject).

The dosage and frequency (single or multiple doses) of compoundadministered can vary depending upon a variety of factors, includingroute of administration; size, age, sex, health, body weight, body massindex, and diet of the recipient; nature and extent of symptoms of thedisease being treated (e.g., a disease responsive to Hsp70 inhibition);presence of other diseases or other health-related problems; kind ofconcurrent treatment; and complications from any disease or treatmentregimen. Other therapeutic regimens or agents can be used in conjunctionwith the methods and compounds of the invention.

For any compound described herein, the therapeutically effective amountcan be initially determined from cell culture assays. Targetconcentrations will be those concentrations of active compound(s) thatare capable of decreasing enzymatic activity as measured, for example,using the methods described.

Therapeutically effective amounts for use in humans may be determinedfrom animal models. For example, a dose for humans can be formulated toachieve a concentration that has been found to be effective in animals.The dosage in humans can be adjusted by monitoring inhibition andadjusting the dosage upwards or downwards, as described above. Incertain embodiments, the administered dose is in the range of about 1 mgto about 1000 mg per day, either once, twice, or more than twice daily.In certain embodiments, the administered dose is in the range of about0.001 to about 100 mg per kilogram per day. In certain embodiments, theadministered dose is in the range of about 0.001 to about 10 mg perkilogram per day. In certain embodiments, the administered dose is inthe range of about 0.0001 to about 100 mg per kilogram per day. Incertain embodiments, the administered dose is in the range of about0.0001 to about 10 mg per kilogram per day. In certain embodiments, theadministered dose is in the range of about 0.01 to about 10 mg perkilogram per day.

In certain embodiments, the preferred therapeutically effective dosagewill be the amount of a compound of the present subject matter requiredto obtain a serum, but more preferably tumor, concentration equivalentto the concentration to achieve phenotypic effects in any of the assaysdescribed herein, such as but not limited to induction of apoptosis asindicated by caspase. In some embodiments, such concentrations areselected from the group consisting of less than 200 uM; less than 100uM; less than 50 uM; less than 25 uM; less than 15 uM; less than 10 uM;less than 5 uM; less than 2 uM; less than 1 uM; less than 500 nM; lessthan 200 nM; or less than 100 nM. In some embodiments, the phenotypiceffect is the IC50 value for an assay.

Dosages may be varied depending upon the requirements of the patient andthe compound being employed. The dose administered to a patient, in thecontext of the present invention, should be sufficient to effect abeneficial therapeutic response in the patient over time. The size ofthe dose also will be determined by the existence, nature, and extent ofany adverse side effects. Generally, treatment is initiated with smallerdosages, which are less than the optimum dose of the compound.Thereafter, the dosage is increased by small increments until theoptimum effect under circumstances is reached. In some embodiments, thedosage range is 0.001% to 10% w/v. In some embodiments, the dosage rangeis 0.1% to 5% w/v.

Dosage amounts and intervals can be adjusted individually to providelevels of the administered compound effective for the particularclinical indication being treated. This will provide a therapeuticregimen that is commensurate with the severity of the individual'sdisease state.

In some embodiments, pharmaceutical compositions in accordance with thesubject matter described herein may be an intravenous form or an oraldosage form, for example, a capsule, a tablet, liquid, and/or a powderpackaged in, for example, a multi-use or single-use package, includingfor example, a container or bottle, a blister package. Single dosagekits and packages containing once per day, or once per treatment, amountof the pharmaceutical composition may be prepared. Single dose, unitdose, and once-daily disposable containers of the present pharmaceuticalcompositions are contemplated as within the scope of the present subjectmatter.

Combination Therapy

In some embodiments, the present pharmaceutical compositions may be usedin combination with an additional pharmaceutical dosage form to enhancetheir effectiveness in treating a disease, disorder, or condition asdescribed herein. In this regard, the present compositions may beadministered as part of a regimen additionally including any otherpharmaceutical and/or pharmaceutical dosage form known in the art aseffective for the treatment of a disease, disorder, or condition asdescribed herein. Similarly, a pharmaceutically active ingredient otherthan those specified herein can be added to the present compositions toenhance their effectiveness in treating a disease, disorder, orcondition as described herein. Accordingly, this additionalpharmaceutically active ingredient or additional pharmaceutical dosageform can be administered to a patient either directly or indirectly, andconcomitantly or sequentially, with the compositions described herein.

For example, other therapies, pharmaceutical dosage forms and/oranticancer agents that may be used in combination with the providedcompounds and compositions of the present invention include surgery,radiotherapy (-radiation, neutron beam radiotherapy, electron beamradiotherapy, proton therapy, brachytherapy, and systemic radioactiveisotopes, to name a few), endocrine therapy, biologic response modifiers(interferons, interleukins, and tumor necrosis factor (TNF) to name afew), hyperthermia and cryotherapy, agents to attenuate any adverseeffects (e.g., antiemetics), and other approved chemotherapeutic drugs,including, but not limited to, alkylating drugs (mechlorethamine,chlorambucil, Cyclophosphamide, Melphalan, Ifosfamide), antimetabolites(Methotrexate), purine antagonists and pyrimidine antagonists(6-Mercaptopurine, 5-Fluorouracil, Cytarabile, Gemcitabine), spindlepoisons (Vinblastine, Vincristine, Vinorelbine, Paclitaxel),podophyllotoxins (Etoposide, Irinotecan, Topotecan), antibiotics(Doxorubicin, Bleomycin, Mitomycin), nitrosoureas (Carmustine,Lomustine), inorganic ions (Cisplatin, Carboplatin), enzymes(Asparaginase), and hormones (Tamoxifen, Leuprolide, Flutamide, andMegestrol), to name a few. In certain embodiments, an anticancer agentis an epothilone, taxol, radicicol or TMC-95A/B. In certain embodiments,the epothilone is 12,13-desoxyepothilone B,(E)-9,10-dehydro-12,13-desoxyEpoB and26-CF3-(E)-9,10-dehydro-12,13-desoxyEpoB. Additionally, the presentinvention also encompasses the use of certain cytotoxic or anticanceragents currently in clinical trials and which may ultimately be approvedby the FDA (including, but not limited to, epothilones and analoguesthereof and geldanamycins and analogues thereof).

In some embodiments, a provided compound is administered in combinationwith one or more other anticancer agents. In some embodiments, ananticancer agent is selected from the group consisting of mitoticinhibitors, alkylating agents, anti-metabolites, intercalatingantibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes,topoisomerase inhibitors, biological response modifiers, anti-hormones,angiogenesis inhibitors, and anti-androgens. Non-limiting examples arechemotherapeutic agents, cytotoxic agents, and non-peptide smallmolecules such as Gleevec (Imatinib Mesylate), Velcade (bortezomib),Casodex (bicalutamide), Iressa (gefitinib), and Adriamycin as well as ahost of chemotherapeutic agents. Non-limiting examples ofchemotherapeutic agents include alkylating agents such as thiotepa andcyclosphosphamide (CYTOXAN™); alkyl sulfonates such as busulfan,improsulfan and piposulfan; aziridines such as benzodopa, carboquone,meturedopa, and uredopa; ethylenimines and methylamelamines includingaltretamine, triethylenemelamine, trietylenephosphoramide,triethylenethiophosphaoramide and trimethylolomelamine; nitrogenmustards such as chlorambucil, chlornaphazine, cholophosphamide,estramustine, ifosfamide, mechlorethamine, mechlorethamine oxidehydrochloride, melphalan, novembichin, phenesterine, prednimustine,trofosfamide, uracil mustard; nitrosureas such as carmustine,chlorozotocin, fotemustine, lomustine, nimustine, ranimustine;antibiotics such as aclacinomysins, actinomycin, authramycin, azaserine,bleomycins, cactinomycin, calicheamicin, carabicin, caminomycin,carzinophilin, Casodex™, chromomycins, dactinomycin, daunorubicin,detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin,esorubicin, idarubicin, marcellomycin, mitomycins, mycophenolic acid,nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin,quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin,ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexateand 5-fluorouracil (5-FU); folic acid analogues such as denopterin,methotrexate, pteropterin, trimetrexate; purine analogs such asfludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidineanalogs such as ancitabine, azacitidine, 6-azauridine, carmofur,cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine,androgens such as calusterone, dromostanolone propionate, epitiostanol,mepitiostane, testolactone; anti-adrenals such as aminoglutethimide,mitotane, trilostane; folic acid replenisher such as frolinic acid;aceglatone; aldophosphamide glycoside; aminolevulinic acid; amsacrine;bestrabucil; bisantrene; edatraxate; defofamine; demecolcine;diaziquone; elfomithine; elliptinium acetate; etoglucid; galliumnitrate; hydroxyurea; lentinan; lonidamine; mitoguazone; mitoxantrone;mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; podophyllinicacid; 2-ethylhydrazide; procarbazine; PSK®; razoxane; sizofuran;spirogermanium; tenuazonic acid; triaziquone;2,2′,2″-trichlorotriethylamine; urethan; vindesine; dacarbazine;mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine;arabinoside (“Ara-C”); cyclophosphamide; thiotepa; taxanes, e.g.paclitaxel (e.g., TAXOL™, Bristol-Myers Squibb Oncology, Princeton,N.J.; ABRAXANE™, Celgene Corporation, Summit, N.J.), and docetaxel(TAXOTERE™, Rhone-Poulenc Rorer, Antony, France); retinoic acid;esperamicins; capecitabine; and pharmaceutically acceptable salts, acidsor derivatives of any of the above. Also included as suitable agents forcombination are suitable chemotherapeutic cell conditioners such asanti-hormonal agents that act to regulate or inhibit hormone action ontumors, including anti-estrogens, e.g., tamoxifen (Nolvadex™),raloxifene, aromatase inhibiting 4(5)-imidazoles, 4-hydroxytamoxifen,trioxifene, keoxifene, LY 117018, onapristone, and toremifene(Fareston); and anti-androgens such as flutamide, nilutamide,bicalutamide, leuprolide, and goserelin. Additional anticancer agentsfor combination include chlorambucil; gemcitabine; 6-thioguanine;mercaptopurine; methotrexate; platinum analogs such as cisplatin andcarboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide;mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbine;novantrone; teniposide; daunomycin; aminopterin; xeloda; ibandronate;camptothecin-11 (CPT-11); topoisomerase inhibitor RFS 2000;difluoromethylornithine (DMFO). In some embodiments, the compounds orpharmaceutical composition of the present invention can be used incombination with commonly prescribed anti-cancer drugs such asHerceptin®, Avastin®, Erbitux®, Rituxan®, Taxol®, Arimidex®, Taxotere®,and Velcade®.

In some embodiments, anti-cancer, anti-malignancy, or anti-proliferativedisorder agents other than compounds discussed above are additionallycontemplated as useful for combination therapy discussed herein.Combinations of any of the foregoing agents or their pharmaceuticallyacceptable salts or derivatives are contemplated herein.

In some embodiments, the present compositions and the additionalpharmaceutical dosage form can be administered to a patient at the sametime. In certain embodiments, one of the present compositions and theadditional pharmaceutical dosage form can be administered in the morningand the other can be administered in the evening.

In some embodiments, the presently described compounds can beadministered to a patient in need thereof in multiple pharmaceuticaldosage forms. This combination therapy may maximize the effectiveness ofthe present composition in treating a cancer, malignancy, orproliferative disorder.

The following numbered embodiments, while non-limiting, are exemplary ofcertain aspects of the present disclosure:

1. A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:

-   -   X is —N═ or —CH═;    -   X¹ is —N═ or —C(R⁵)═;    -   R^(1b) is

-   -   R^(1a) is

or C₁₋₆ aliphatic optionally substituted with one or more groupsindependently selected from —OH, cyclopropyl, or 5-membered heteroarylhaving 1-2 heteroatoms independently selected from nitrogen, oxygen orsulfur;

-   -   each R^(1b) is independently hydrogen, C₁₋₄ alkyl, or two R^(1b)        groups are optionally taken together to form an oxo group;    -   each of R^(1c) and R^(1d) is independently hydrogen or C₁₋₄        alkyl;    -   R² is —O—CH₂-Ring A, —NH—CH₂-Ring A, or —O—CH₂CH₂-Ring A;    -   Ring A is unsubstituted phenyl, unsubstituted furanyl,

or pyridinyl optionally substituted with R^(A5);

-   -   each of R^(A1) is independently halogen, —CN, —C(O)N(R)₂,        —N(R)₂, —OR, —C(O)R, —N₃, an optionally substituted 5- or        6-membered heterocyclyl or heteroaryl having one or two        heteroatoms independently selected from nitrogen, oxygen, or        sulfur, or C₁₋₄ alkyl optionally substituted with one or more        halogen;    -   each R is independently hydrogen or C₁₋₄ alkyl optionally        substituted with one or more halogen;    -   R^(A2) is —Cl, —Br, —I, —CN, —C(O)N(R)₂, —N(R)₂, —OR, —C(O)R,        —N₃, C₁₋₄ alkyl optionally substituted with one or more halogen,        or an optionally substituted 5- or 6-membered heterocyclyl or        heteroaryl having one or two heteroatoms independently selected        from nitrogen, oxygen or sulfur;    -   n is 1 to 4;    -   R^(A3) is —H or —F;    -   R^(A4) is —F or —OR;    -   R^(A5) is —OR or —N(R)₂;    -   R³ is —C(O)N(R^(3a))₂, —OR^(3b), —C(O)H, —C(O)OR, or        —N(R^(3c))₂;    -   each R^(3a) is independently hydrogen or C₁ alkyl optionally        substituted with one or more groups independently selected from        halogen or 1-pyrrolidinyl;    -   R^(3b) is hydrogen or C₁₋₄ alkyl optionally substituted with one        or more groups independently selected from halogen, C₁₋₄ alkyl,        C₁₋₄ haloalkyl, oxo, or —N(R)₂;    -   each R^(3c) is independently hydrogen or C₁₋₄ alkyl optionally        substituted with one or more groups independently selected from        halogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, oxo, or —N(R)₂;    -   R⁴ is R, halogen, or —N(R)₂; and    -   R⁵ is hydrogen, methyl or —N(R)₂.        2. The compound of embodiment 1, wherein X is —N═.        3. The compound of embodiment 1, wherein X is —CH═.        4. The compound of any one of the preceding embodiments, wherein        R³ is —C(O)N(R^(3a))₂.        5. The compound of any one of the preceding embodiments, wherein        R³ is —C(O)NH₂.        6. The compound of embodiment 4, wherein one R^(3a) is hydrogen,        and the other R^(3a) is C₁ alkyl optionally substituted with one        or more groups independently selected from halogen or        1-pyrrolidinyl.        7. The compound of embodiment 4, wherein each R^(3a) is methyl.        8. The compound of any one of embodiments 1-3, wherein R³ is        —OR^(3b).        9. The compound of embodiment 8, wherein R^(3b) is hydrogen.        10. The compound of embodiment 8, wherein R^(3b) is C₁₋₄ alkyl        optionally substituted with one or more groups independently        selected from halogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, oxo, or        —N(R)₂.        11. The compound of embodiment 8, wherein R^(3b) is C₁₋₄ alkyl.        12. The compound of embodiment 11, wherein R^(3b) is methyl.        13. The compound of embodiment 10, wherein R^(3b) is        —CH(CH₃)C(O)NH₂.        14. The compound of any one of embodiments 1-5, wherein R³ is        —C(O)H.        15. The compound of any one of embodiments 1-5, wherein R³ is        —C(O)OR.        16. The compound of any one of embodiments 1-5, wherein R³ is        —N(R^(3c))₂.        17. The compound of embodiment 16, wherein each R^(3c) is        hydrogen.        18. The compound of embodiment 16, wherein one R^(3c) is        hydrogen, and the other R^(3c) is C₁₋₄ alkyl optionally        substituted with one or more groups independently selected from        halogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, oxo, or —N(R)₂;        19. The compound of any one of the preceding embodiments,        wherein R⁴ is R or halogen.        20. The compound of any one of the preceding embodiments,        wherein R⁴ is R.        21. The compound of any one of the preceding embodiments,        wherein R⁴ is hydrogen.        22. The compound of any one of embodiments 1-20, wherein R⁴ is        C₁₋₄ alkyl.        23. The compound of embodiment 22, wherein R⁴ is methyl.        24. The compound of any one of embodiments 1-19, wherein R⁴ is        C₁₋₄ alkyl optionally substituted with one or more halogen.        25. The compound of embodiment 24, wherein R⁴ is —CF₃.        26. The compound of any one of embodiments 1-19, wherein R⁴ is        halogen.        27. The compound of any one of embodiments 1-19, wherein R⁴ is        —F.        28. The compound of any one of embodiments 1-19, wherein R⁴ is        —Cl.        29. The compound of any one of embodiments 1-19, wherein R⁴ is        —Br.        30. The compound of any one of embodiments 1-19, wherein R⁴ is        —I.        31. The compound of any one of the preceding embodiments,        wherein X¹ is —C(R⁵)═.        32. The compound of any one of the preceding embodiments,        wherein R⁵ is hydrogen.        33. The compound of any one of embodiments 1-31, wherein R⁵ is        methyl.        34. The compound of any one of embodiments 1-31, wherein R⁵ is        —NH₂.        35. The compound of any one of embodiments 1-30, wherein X¹ is        —N═.        36. The compound of embodiment 1, wherein

is a group selected from Table 4.37. A compound of formula II:

or a pharmaceutically acceptable salt thereof, wherein:

-   -   Y is —S—, —O—, or —CR₂—;    -   R¹ is

-   -   R^(1a) is

or C₁₋₆ aliphatic optionally substituted with one or more groupsindependently selected from —OH, cyclopropyl, or 5-membered heteroarylhaving 1-2 heteroatoms independently selected from nitrogen, oxygen, orsulfur;

-   -   each R^(1b) is independently hydrogen, C₁₋₄ alkyl, or two R^(1b)        groups are optionally taken together to form an oxo group;    -   each of R^(1c) and R^(1d) is independently hydrogen or C₁₋₄        alkyl;    -   R² is —O—CH₂-Ring A, —NH—CH₂-Ring A, or —O—CH₂CH₂-Ring A;    -   Ring A is unsubstituted phenyl, unsubstituted furanyl,

or pyridinyl optionally substituted with R^(A5)

-   -   each of R^(A1) is independently halogen, —CN, —C(O)N(R)₂,        —N(R)₂, —OR, —C(O)R, —N₃, an optionally substituted 5- or        6-membered heterocyclyl or heteroaryl having one or two        heteroatoms independently selected from nitrogen, oxygen, or        sulfur, or C₁₋₄ alkyl optionally substituted with one or more        halogen;    -   each R is independently hydrogen or C₁₋₄ alkyl optionally        substituted with one or more halogen;    -   R^(A2) is —Cl, —Br, —I, —CN, —C(O)N(R)₂, —N(R)₂, —OR, —C(O)R,        —N₃, C₁₋₄ alkyl optionally substituted with one or more halogen,        or an optionally substituted 5- or 6-membered heterocyclyl or        heteroaryl having one or two heteroatoms independently selected        from nitrogen, oxygen or sulfur;    -   n is 1 to 4;    -   R^(A3) is —H or —F;    -   R^(A4) is —F or —OR;    -   R^(A5) is —OR or —N(R)₂; and    -   Ring B is

thienyl optionally substituted with —C(O)R, or furanyl optionallysubstituted with —C(O)R.38. The compound of embodiment 37, wherein Y is —S—.39. The compound of embodiment 37, wherein Y is —O—.40. The compound of embodiment 37, wherein Y is —CH₂—.41. The compound of embodiment 37, wherein Ring B is

42. The compound of any one of the preceding embodiments, wherein R¹ isR¹ is

43. The compound of any one of the preceding embodiments, wherein R¹ is

44. The compound of any one of the preceding embodiments, wherein eachR^(1b) is independently hydrogen, or two R^(1b) groups are optionallytaken together to form an oxo group.45. The compound of any one of the preceding embodiments, wherein R^(1a)is

or C₁₋₄ straight chain aliphatic optionally substituted with one or moregroups independently selected from —OH or 5-membered heteroaryl having1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur.46. The compound of any one of embodiments 1-41, wherein R¹ is

47. The compound of any one of embodiments 1-41, wherein R¹ is

48. The compound of any one of embodiments 1-41, 46, and 47, whereineach R^(1c) is independently C₁₋₄ alkyl.49. The compound of any one of embodiments 1-41, 46, 47 and 48, whereineach R^(1c) is methyl.50. The compound of any one of embodiments 1-41, wherein R¹ is

51. The compound of any one of embodiments 1-41, wherein R¹ is

52. The compound of any one of embodiments 1-41, wherein R¹ is

53. The compound of any one of embodiments 1-41 and 51-52, wherein eachR^(1c) is independently hydrogen or C₁₋₄ alkyl, and R^(1d) isindependently C₁₋₄ alkyl.54. The compound of embodiment 51 or 52, wherein R¹ is

55. The compound of embodiment 51 or 52, wherein R¹ is

56. The compound of any one of embodiments 1-41, wherein R¹ is a groupselected from Table 1.57. The compound of any one of the preceding embodiments, wherein R² is—O—CH₂—Ring A.58. The compound of any one of embodiments 1-56, wherein R² is—NH—CH₂-Ring A.59. The compound of any one of embodiments 1-56, wherein R² is—O—CH₂CH₂-Ring A.60. The compound of any one of embodiments 1-59, wherein Ring A isphenyl.61. The compound of any one of embodiments 1-59, wherein Ring A isfuranyl.62. The compound of any one of embodiments 1-59, wherein Ring A is1-furanyl.63. The compound of any one of embodiments 1-59, wherein Ring A is2-furanyl.64. The compound of any one of embodiments 1-59, wherein Ring A is

65. The compound of embodiment 64, wherein Ring A is

66. The compound of embodiment 65, wherein Ring A is

67. The compound of any one of embodiments 64-66, wherein R^(A1) is —Clor —OR.68. The compound of any one of embodiments 64-67, wherein R^(A1) is —OR,wherein R is C₁₋₄ alkyl.69. The compound of any one of embodiments 64-68, wherein R^(A1) is—OCH₃.70. The compound of any one of embodiments 1-66, wherein R^(A1) is—N(R)₂, wherein each R is independently C₁₋₄ alkyl.71. The compound of any one of embodiments 1-66 and 70, wherein R^(A1)is —N(CH₃)₂.72. The compound of any one of embodiments 1-59, wherein Ring A is

73. The compound of embodiment 72, wherein R^(A2) is —F, —Br, or —OR.74. The compound of embodiment 72 or 73, wherein R^(A2) is —OR, whereinR is C₁₋₄ alkyl.75. The compound of any one of embodiments 72-74, wherein R^(A2) is—OCH₃.76. The compound of any one of embodiments 1-59, wherein Ring A is

77. The compound of embodiment 76, wherein R^(A3) is —H or —F.78. The compound of embodiment 76 or 77, wherein R^(A4) is —F or —OCH₃.79. The compound of any one of embodiments 1-59, wherein Ring A ispyridinyl optionally substituted with R^(A5).80. The compound of any one of embodiments 1-59, wherein Ring A ispyridinyl substituted with R^(A5).81. The compound of embodiment 79 or 80, wherein R^(A5) is —N(R)₂.82. The compound of embodiment 81, wherein R^(A5) is —NH₂.83. The compound of embodiment 79 or 80, wherein R^(A5) is —OR.84. The compound of embodiment 83, wherein R is C₁₋₄ alkyl.85. The compound of embodiment 83 or 84, wherein R is methyl.86. The compound of any of embodiments 1-56, wherein R² is a groupselected from Table 3.87. A compound selected from Table 5, or a pharmaceutically acceptablesalt thereof.88. A compound selected from Table 6, or a pharmaceutically acceptablesalt thereof.89. The compound of any one of the preceding embodiments, wherein thecompound has an activity in a caspase cleaving assay at about 1.0 μM orbelow.90. The compound of any one of the preceding embodiments, wherein thecompound has an activity in a caspase cleaving assay below about 0.5 μM.91. The compound of any one of the preceding embodiments, wherein thecompound has an activity in a caspase cleaving assay below about 0.4 μM.92. The compound of any one of the preceding embodiments, wherein thecompound has an activity in a caspase cleaving assay below about 0.2 μM.93. The compound of any one of the preceding embodiments, wherein thecompound has an activity in a caspase cleaving assay below about 0.1 μM.94. The compound of any one of the preceding embodiments, wherein thecompound has an activity in a caspase cleaving assay below about 0.05μM.95. The compound of any one of the preceding embodiments, wherein thecompound has an activity in a caspase cleaving assay below about 0.01μM.96. A pharmaceutical composition comprising a compound of any one ofembodiments 1-95 and a pharmaceutically acceptable carrier.97. A method of treating a subject suffering from or susceptible to adisease, disorder, or condition responsive to Hsp70 inhibition, themethod comprising administering to the subject a therapeuticallyeffective amount of a compound of any one of embodiments 1-95 or acomposition thereof.98. The method of embodiment 97, wherein the disease, disorder, orcondition is a proliferative disease, disorder, or condition.99. The method of embodiment 98, wherein the disease, disorder, orcondition is cancer.100. The method of embodiment 99, wherein the cancer is refractory totreatment with Hsp90 inhibitors.101. The method of embodiment 99 or 100, further comprisingadministering to the subject a therapeutically effective amount of asecond chemotherapeutic agent.102. The method of any one of embodiments 99-101, wherein the subject isin clinical remission or, where the subject has been treated by surgery,has limited unresected disease.103. A method of inhibiting Hsp70 activity, the method comprisingcontacting Hsp70 with a compound of any one of embodiments 1-95 or acomposition thereof.104. The method of embodiment 103, wherein the method is for the ex vivoinhibition of Hsp70.105. The method of embodiment 103, wherein the method is for theinhibition of Hsp70 in a patient.106. A method for treating or preventing cancer in a subject sufferingtherefrom, the method comprising administering to a patient in needthereof a therapeutically effective amount of a compound of any one ofembodiments 1-95 or a composition thereof.107. The method of embodiment 106, wherein the subject is in clinicalremission or, where the subject has been treated by surgery, has limitedunresected disease.108. The method of embodiment 106 or 107, wherein the cancer isrefractory to treatment with Hsp90 inhibitors.109. A method for activating a caspase in cells, comprisingadministering to the cells a compound of any one of embodiments 1-95 ora composition thereof.110. A method for inducing apoptosis in cells, comprising administeringto the cells a compound of any one of embodiments 1-95 or a compositionthereof.111. A method for inhibiting cell growth, comprising administering tothe cells a compound of any one of embodiments 1-95 or a compositionthereof.112. The method of any one of embodiments 109-111, wherein the cells areresistant to Hsp90 inhibitors.

In order that the invention described herein may be more fullyunderstood, the following examples are set forth. It should beunderstood that these examples are for illustrative purposes only andare not to be construed as limiting this invention in any manner.

EXAMPLES

Chemical Synthesis and Purification

General.

NMR spectra were recorded on a Bruker AV-III-500 or 600 MHz NMRspectrometer. Chemical shifts are reported in δ values in ppm downfieldfrom TMS as the internal standard. ¹H data are reported as follows:chemical shift, multiplicity (s=singlet, d=doublet, t=triplet,q=quartet, br=broad, m=multiplet), coupling constant (Hz), integration.¹³C chemical shifts are reported in δ values in ppm downfield from TMSas the internal standard. High resolution mass spectra were recorded ona Waters LCT Premier system. Low resolution mass spectra were obtainedon Waters Acquity Ultra Performance LC with electrospray ionization andSQ detector. Analytical HPLC was performed on a Waters Autopurificationsystem with PDA, MicroMass ZQ and ELSD detector. Analytical thin layerchromatography was performed on 250 μM silica gel F₂₅₄ plates.Preparative thin layer chromatography was performed on 1000 μM silicagel F₂₅₄ plates. Flash column chromatography was performed employing230-400 mesh silica gel. Solvents were HPLC grade. All reagents werepurchased from Aldrich, Acros, Oakwood or Matrix Scientific and usedwithout purification. All reactions were performed under argonprotection.

Example 1

General Procedure for the Synthesis of 10, 11, 13, 14, 18, 19 and 22-25.

A mixture of aryliodide 9 (1 equiv.), arylthiol (1.2 equiv.) and K₂CO₃(2 equiv.) in DMF was evacuated and backfilled with argon three times.Copper(I)thiophene-2-carboxylate (0.4 equiv.) was added and evacuatedand backfilled with argon two times. The reaction mixture was heated at120° C. for 24 h or 130° C. for 3 h under argon. Solvent was removedunder reduced pressure and the residue was purified by columnchromatography to afford the desired product.

4-(4-(Benzyloxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-ylthio)aniline[10]

10 was obtained in 75% yield following the general procedure above afterheating at 120° C. for 24 h. ¹H NMR (500 MHz, CDCl₃): δ 8.17 (s, 1H),7.20-7.30 (m, 5H), 7.13 (d, J=8.4 Hz, 2H), 6.54 (d, J=8.4 Hz, 2H), 5.37(s, 2H), 3.80 (m, 4H), 3.66 (br s, 2H), 2.42 (m, 4H), 2.32 (s, 3H); ¹³CNMR (125 MHz, CDCl₃): δ 167.8, 162.4, 161.0, 158.1, 145.7, 136.8, 132.4,128.3, 127.7, 127.5, 123.9, 115.6, 67.6, 54.8, 46.2, 43.9; HRMS (ESI)m/z [M+H]⁺ calcd. for C₂₂H₂₆N₅OS, 408.1858; found 408.1839.

5-((4-(Benzyloxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)-2-methoxyaniline[11]

11 was obtained in 64% yield following the general procedure above afterheating at 120° C. for 24 h. ¹H NMR (500 MHz, CDCl₃) δ 8.20 (s, 1H),7.22-7.28 (m, 5H), 6.61-6.67 (m, 2H), 6.58 (s, 1H), 5.38 (s, 2H),3.81-3.83 (m, 4H), 3.80 (s, 3H), 3.69 (br s, 2H), 2.43-2.45 (m, 4H),2.33 (s, 3H); ¹³C NMR (125 MHz, CDCl₃): 168.3, 163.4, 161.3, 146.6,137.0, 136.9, 128.5, 127.9, 127.8, 127.7, 120.0, 116.3, 110.9, 102.7,67.8, 55.8, 55.0, 46.4, 44.0; MS (m/z): [M+H]⁺ 438.2.

3-((4-(Benzyloxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)pyridin-2-amine[13]

13 was obtained in 26% yield following the general procedure above afterheating at 120° C. for 24 h. ¹H NMR (500 MHz, CDCl₃) δ 8.19 (s, 1H),7.95 (d, J=6.5 Hz, 1H), 7.51 (d, J=7.5 Hz, 1H), 7.31-7.36 (m, 5H), 6.50(dd, J=7.5, 5.2 Hz, 1H), 5.36 (s, 2H), 5.01 (br s, 2H), 3.82-3.84 (m,4H), 2.44-2.46 (m, 4H), 2.34 (s, 3H); HRMS (ESI) m/z [M+H]⁺ calcd. forC₂₁H₂₅N₆OS, 409.1811; found 409.1804.

4-(Benzyloxy)-5-((6-methoxy-5-nitropyridin-3-yl)thio)-2-(4-methylpiperazin-1-yl)pyrimidine[14]

14 was obtained in 63% yield following the general procedure above afterheating at 120° C. for 24 h. ¹H NMR (500 MHz, CDCl₃) δ 8.19 (s, 2H),7.60 (s, 1H), 7.19-7.31 (m, 5H), 5.27 (s, 2H), 3.77-3.79 (m, 4H), 3.22(s, 3H), 2.37-2.39 (m, 4H), 2.27 (s, 3H); ¹³C NMR (125 MHz, CDCl₃):168.2, 162.7, 161.5, 153.9, 148.5, 143.0, 138.0, 136.1, 128.9, 128.8,128.5, 110.2, 101.0, 68.5, 54.9, 46.3, 44.0, 38.6; HRMS (ESI) m/z [M+H]⁺calcd. for C₂₂H₂₅N₆O₄S, 469.1658; found 469.1662.

4-((4-(Benzyloxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)-3-methylbenzonitrile[18]

18 was obtained in 76% yield following the general procedure above afterheating at 120° C. for 24 h. ¹H NMR (500 MHz, CDCl₃): δ 8.24 (s, 1H),7.39 (s, 1H), 7.12-7.32 (m, 6H), 6.76 (d, J=8.2 Hz, 1H), 5.39 (s, 2H),3.86-3.94 (m, 4H), 2.46-2.52 (m, 4H), 2.43 (s, 3H), 2.38 (s, 3H); ¹³CNMR (125 MHz, CDCl₃): δ 168.7, 165.2, 161.8, 144.7, 136.3, 135.7, 132.8,129.6, 128.4, 128.0, 127.6, 125.4, 119.2, 107.8, 96.6, 67.8, 54.8, 46.2,43.9, 19.7; HRMS (ESI) m/z [M+H]⁺ calcd. for C₂₄H₂₆N₅OS, 432.1858; found432.1840.

4-((4-(Benzyloxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)-2-methylbenzonitrile[19]

19 was obtained in 78% yield following the general procedure above afterheating at 120° C. for 24 h. ¹H NMR (500 MHz, CDCl₃): δ 8.24 (s, 1H),7.36 (d, J=8.1 Hz, 1H), 7.23-7.30 (m, 3H), 7.11-7.18 (m, 2H), 6.96 (s,1H), 6.90 (d, J=8.0 Hz, 1H), 5.30 (s, 2H), 3.85-3.93 (m, 4H), 2.44-2.50(m, 4H), 2.41 (s, 3H), 2.35 (s, 3H); ¹³C NMR (125 MHz, CDCl₃): δ 168.6,165.0, 161.7, 145.2, 142.1, 136.3, 132.5, 128.4, 128.0, 127.5, 127.1,123.5, 118.3, 108.9, 97.1, 67.8, 54.8, 46.2, 43.9, 20.4; HRMS (ESI) m/z[M+H]⁺ calcd. for C₂₄H₂₆N₅OS, 432.1858; found 432.1840.

4-((4-(Benzyloxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)-2-bromobenzonitrile[22]

22 was obtained in 52% yield following the general procedure above afterheating at 120° C. for 24 h. ¹H NMR (500 MHz, CDCl₃): δ 8.22 (s, 1H),7.38 (d, J=8.2 Hz, 1H), 7.24-7.31 (m, 4H), 7.14-7.19 (m, 2H), 6.85-7.04(m, 1H), 5.37 (s, 2H), 3.83-3.97 (m, 4H), 2.44-2.54 (m, 4H), 2.37 (s,3H); ¹³C NMR (125 MHz, CDCl₃): δ 168.5, 165.1, 161.8, 147.6, 136.1,133.8, 129.2, 128.5, 128.1, 127.5, 125.5, 124.6, 117.4, 111.4, 95.9,68.0, 54.7, 46.1, 43.9; HRMS (ESI) m/z [M+H]⁺ calcd. for C₂₃H₂₂BrN₅OS,496.0807; found 496.0816.

4-((4-(Benzyloxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)-2-chlorobenzonitrile[23]

23 was obtained in 39% yield following the general procedure above afterheating at 120° C. for 24 h. ¹H NMR (500 MHz, CDCl₃): δ 8.22 (s, 1H),7.39 (d, J=8.3 Hz, 1H), 7.25-7.31 (m, 3H), 7.15-7.20 (m, 2H), 7.10 (d,J=1.7 Hz, 1H), 6.98 (dd, J=8.3, 1.7 Hz, 1H), 5.37 (s, 2H), 3.86-3.95 (m,4H), 2.45-2.54 (m, 4H), 2.36 (s, 3H); ¹³C NMR (125 MHz, CDCl₃): δ 168.5,165.1, 161.8, 147.7, 137.1, 136.1, 133.5, 128.5, 128.1, 127.6, 126.2,124.1, 116.2, 109.0, 95.9, 68.0, 54.7, 46.1, 43.9; HRMS (ESI) m/z [M+H]⁺calcd. for C₂₃H₂₂ClN₅OS, 452.1312; found 452.1303.

4-((4-(Benzyloxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)-2-fluorobenzonitrile[24]

24 was obtained in 92% yield following the general procedure above afterheating at 130° C. for 3 h. MS (ESI) m/z [M+H]⁺ 436.3.

4-((4-(Benzyloxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)-2-iodobenzonitrile[25]

25 was obtained in 57% yield following the general procedure above afterheating at 130° C. for 3 h. MS (ESI) m/z [M+H]⁺ 544.2.

Example 2

4-(Benzyloxy)-5-((4-methoxybenzyl)thio)-2-(4-methylpiperazin-1-yl)pyrimidine[26]

A mixture of 9 (0.400 g, 1.0 mmol) and K₂CO₃ (0.552 g, 4.0 mmol) in DMF(10 mL) was evacuated and backfilled with argon three times.Copper(I)thiophene-2-carboxylate (0.076 g, 0.4 mmol) and CuI (0.078 g,0.4 mmol) was added and evacuated and backfilled with argon two times.(4-Methoxyphenyl)methanethiol (0.185 g, 1.2 mmol) was added and thereaction mixture was heated at 135° C. for 18 h. Solvent was removedunder reduced pressure and the residue was purified by columnchromatography (CH₂Cl₂:MeOH, 0-10% MeOH) to afford 0.340 mg (78%) of 26.HRMS (ESI) m/z [M+H]⁺ calcd. for C₂₄H₂₉N₄O₂S, 437.2011; found 437.2025.

bis((4-(Benzyloxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)mercury[27]

To a solution of 26 (5.0 g, 11.5 mmol) in TFA (30 mL) was added HgO(1.25 g, 5.7 mmol) and the mixture stirred for 1 h at rt. The reactionmixture was concentrated under reduced pressure and the resultingresidue was purified by column chromatography (CH₂Cl₂:MeOH, 9:1) toafford 4.5 g (95%) of 27. ¹H NMR (500 MHz, CDCl₃): δ 8.10 (s, 2H),7.26-7.38 (m, 10H), 5.32 (s, 4H), 3.86 (m, 8H), 2.61 (m, 8H), 2.40 (s,6H); MS (m/z): [M+H]⁺ 483.1.

General Procedure for Synthesis of 29-32, 36, 37, 40, 43-45, 47-49.

The mixture of 27 (1 equiv.), aryliodide (1.2 equiv.), K₂CO₃ (4 equiv.),neocuproine (0.5 equiv.) and CuI (1 equiv.) in DMF was heated at 135° C.for 1.5 h under argon. Solvent was removed under reduced pressure andthe residue was purified by column chromatography to afford the desiredproduct.

5-((4-(Benzyloxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)furan-2-carbaldehyde[29]

29 was obtained in 72% yield following the general procedure above. ¹HNMR (500 MHz, CDCl₃): δ 9.45 (s, 1H), 8.27 (s, 1H), 7.30 (m, 5H), 7.10(d, J=3.6 Hz, 1H), 6.31 (d, J=3.2 Hz, 1H), 5.39 (s, 2H), 3.85 (m, 4H),2.45 (m, 4H), 2.33 (s, 3H); ¹³C NMR (125 MHz, CDCl₃): δ 176.6, 168.0,163.9, 161.5, 155.7, 153.8, 136.3, 128.4, 128.0, 127.6, 122.2, 113.7,96.7, 68.0, 54.8, 46.2, 43.9; HRMS (ESI) m/z [M+H]⁺ calcd. forC₂₁H₂₃N₄O₃S, 411.1491; found 411.1510.

1-(5-((4-(Benzyloxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)thiophen-2-yl)ethanone[30]

30 was obtained in 68% yield following the general procedure above. ¹HNMR (500 MHz, CDCl₃): δ 8.26 (s, 1H), 7.45 (d, J=3.9 Hz, 1H), 7.25-7.32(m, 5H), 6.90 (d, J=3.9 Hz, 1H), 5.39 (s, 2H), 3.84-3.90 (m, 4H),2.44-2.49 (m, 7H), 2.35 (s, 3H); ¹³C NMR (125 MHz, CDCl₃): δ 189.6,168.0, 164.1, 161.5, 150.4, 143.7, 136.3, 133.0, 128.4, 127.9, 127.6,127.3, 100.1, 68.0, 54.8, 46.2, 43.9, 26.3; HRMS (ESI) m/z [M+H]⁺ calcd.for C₂₂H₂₅N₄O₂S₂, 441.1419; found 441.1418.

6-((4-(Benzyloxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)pyridin-3-amine[31]

31 was obtained in 65% yield following the general procedure above. ¹HNMR (500 MHz, CDCl₃): δ 8.27 (s, 1H), 7.92 (s, 1H), 7.17-7.30 (m, 5H),6.79 (s, 2H), 5.37 (s, 2H), 3.80-3.88 (m, 4H), 3.59 (br s, 2H),2.42-2.49 (m, 4H), 2.34 (s, 3H); HRMS (ESI) m/z [M+H]⁺ calcd. forC₂₁H₂₅N₆OS, 409.1811; found 409.1806.

5-((4-(Benzyloxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)pyridin-2-amine[32]

32 was obtained in 59% yield following the general procedure above. ¹HNMR (500 MHz, CDCl₃): δ 8.20 (s, 1H), 8.12 (s, 1H), 7.36-7.42 (m, 1H),7.23-7.36 (m, 5H), 6.33 (d, J=8.5 Hz, 1H), 5.36 (s, 2H), 4.49 (br s,2H), 3.77-3.84 (m, 4H), 2.38-2.47 (m, 4H), 2.37 (s, 3H); HRMS (ESI) m/z[M+H]⁺ calcd. for C₂₁H₂₅N₆OS, 409.1811; found 409.1810.

1-(4-((4-(Benzyloxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)phenyl)ethanone[36]

36 was obtained in 52% yield following the general procedure above. ¹HNMR (500 MHz, CDCl₃): δ 8.26 (s, 1H), 7.77 (d, J=8.5 Hz, 2H), 7.23 (m,3H), 7.14 (m, 2H), 7.12 (d, J=8.5 Hz, 2H), 5.36 (s, 2H), 3.88 (m, 4H),2.54 (s, 3H), 2.47 (m, 4H), 2.35 (s, ³H); ¹³C NMR (125 MHz, CDCl₃): δ197.2, 168.6, 165.0, 161.7, 145.3, 136.4, 134.0, 128.7, 128.3, 127.8,127.4, 125.7, 97.7, 67.8, 54.8, 46.2, 43.9, 26.5; HRMS (ESI) m/z [M+H]⁺calcd. for C₂₄H₂₇N₄O₂S, 435.1855; found 435.1866.

4-((4-(Benzyloxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)phenol[37]

37 was obtained in 54% yield following the general procedure above. ¹HNMR (500 MHz, CDCl₃): δ 8.15 (s, 1H), 7.26 (m, 3H), 7.25 (m, 2H), 7.16(d, J=8.5 Hz, 2H), 6.05 (d, J=8.5 Hz, 2H), 5.34 (s, 2H), 3.82 (m, 4H),2.48 (m, 4H), 2.35 (s, 3H); ¹³C NMR (125 MHz, CDCl₃): δ 167.9, 162.3,160.9, 155.8, 136.5, 132.3, 128.3, 127.8, 127.5, 125.9, 116.2, 103.6,67.8, 54.7, 46.0, 43.6; HRMS (ESI) m/z [M+H]⁺ calcd. for C₂₂H₂₅N₄O₂S,409.1698; found 409.1696.

4-(Benzyloxy)-5-((4-methoxy-2-nitrophenyl)thio)-2-(4-methylpiperazin-1-yl)pyrimidine[40]

40 was obtained in 59% yield following the general procedure above. ¹HNMR (500 MHz, CDCl₃): δ 8.26 (s, 1H), 7.72 (d, J=2.7 Hz, 1H), 7.22-7.28(m, 3H), 7.12-7.18 (m, 2H), 6.91 (dd, J=9.0, 2.8 Hz, 1H), 6.81 (d, J=9.0Hz, 1H), 5.35 (s, 2H), 3.86-3.94 (m, 4H), 3.84 (s, 3H), 2.46-2.51 (m,4H), 2.36 (s, 3H); HRMS (ESI) m/z [M+H]⁺ calcd. for C₂₃H₂₆N₅O₄S,468.1706; found 468.1697.

3-((4-(Benzyloxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)benzaldehyde[43]

43 was obtained in 59% yield following the general procedure above. ¹HNMR (500 MHz, CDCl₃): δ 9.86 (s, 1H), 8.29 (s, 1H), 7.63 (d, J=7.2 Hz,1H), 7.57 (s, 1H), 7.38 (m, 2H), 7.22 (m, 3H), 7.11 (m, 2H), 5.34 (s,2H), 4.04 (m, 4H), 2.80 (m, 4H), 2.56 (s, ³H); ¹³C NMR (125 MHz, CDCl₃):δ 191.8, 168.6, 164.5, 161.3, 139.4, 130.9, 136.2, 132.9, 129.4, 128.4,128.0, 127.9, 127.4, 126.9, 99.7, 68.0, 54.2, 45.3, 42.7; HRMS (ESI) m/z[M+H]⁺ calcd. for C₂₃H₂₅N₄O₂S, 421.1698; found 421.1703.

4-((4-(Benzyloxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)benzonitrile[44]

44 was obtained in 72% yield following the general procedure above. ¹HNMR (500 MHz, CDCl₃): δ 8.24 (s, 1H), 7.42 (d, J=8.5 Hz, 2H), 7.25 (m,3H), 7.13 (m, 2H), 7.10 (d, J=8.5 Hz, 2H), 5.36 (s, 2H), 3.95 (m, 4H),2.60 (m, 4H), 2.40 (s, 3H); ¹³C NMR (125 MHz, CDCl₃): δ 168.0, 165.0,161.7, 145.5, 136.1, 132.1, 128.4, 128.0, 127.5, 126.2, 118.9, 108.3,97.3, 67.9, 54.2, 45.4, 43.2; HRMS (ESI) m/z [M+H]⁺ calcd. forC₂₃H₂₄N₅OS, 418.1702; found 418.1713.

4-((4-(Benzyloxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)benzaldehyde[45]

45 was obtained in 52% yield following the general procedure above. ¹HNMR (500 MHz, CDCl₃): δ 9.90 (s, 1H), 8.26 (s, 1H), 7.67 (d, J=8.3 Hz,2H), 7.11-7.28 (m, 7H), 5.37 (s, 2H), 3.86-3.96 (m, 4H), 2.45-2.53 (m,4H), 2.35 (s, 3H); ¹³C NMR (125 MHz, CDCl₃): δ 191.2, 168.7, 165.1,161.7, 147.4, 136.3, 133.5, 130.0, 128.3, 127.9, 127.5, 125.8, 97.2,67.8, 54.8, 46.2, 43.9; HRMS (ESI) m/z [M+H]⁺ calcd. for C₂₃H₂₅N₄O₂S,421.1698; found 421.1690.

3-((4-(Benzyloxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)benzonitrile[47]

47 was obtained in 70% yield following the general procedure above. ¹HNMR (500 MHz, CDCl₃): δ 8.27 (s, 1H), 7.37 (t, J=7.3 Hz, 1H), 7.36 (d,J=8.6 Hz, 1H), 7.23-7.33 (m, 5H), 7.14-7.18 (m, 2H), 5.37 (s, 2H),3.85-3.91 (m, 4H), 2.37-2.61 (m, 4H), 2.37 (s, 3H); ¹³C NMR (125 MHz,CDCl₃): δ 168.5, 164.9, 161.6, 140.5, 136.2, 130.8, 129.5, 129.2, 128.7,128.4, 128.0, 127.4, 118.5, 112.9, 97.4, 67.9, 54.8, 46.2, 43.9; MS(m/z): 418.2 [M+H]⁺.

6-((4-(Benzyloxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)nicotinonitrile[48]

48 was obtained in 65% yield following the general procedure above. ¹HNMR (500 MHz, CDCl₃): δ 8.57 (s, 1H), 8.25 (s, 1H), 7.59 (d, J=8.3 Hz,1H), 7.21-7.31 (m, 5H), 6.98 (d, J=8.4 Hz, 1H), 5.40 (s, 2H), 3.90-3.94(m, 4H), 2.45-2.52 (m, 4H), 2.38 (s, 3H); ¹³C NMR (125 MHz, CDCl₃): δ168.5, 166.9, 164.9, 161.8, 152.1, 138.4, 136.3, 128.4, 128.0, 127.6,119.8, 116.9, 104.9, 95.7, 67.8, 54.8, 46.2, 43.9; MS (m/z): 419.1[M+H]⁺.

Methyl4-((4-(benzyloxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)benzoate[49]

49 was obtained in 72% yield following the general procedure above. ¹HNMR (500 MHz, CDCl₃, TMS) δ 8.26 (s, 1H), 7.84 (d, J=8.6 Hz, 2H), 7.23(m, 3H), 7.11 (m, 4H), 5.36 (s, 2H), 3.89 (m, 7H), 2.48 (m, 4H), 2.36(s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 168.6, 166.8, 165.0, 161.7, 144.9,136.4, 129.9, 128.3, 127.8, 127.4, 126.8, 125.6, 97.9, 67.8, 54.8, 52.0,46.2, 43.9; MS (m/z): 451.1 [M+H]⁺.

Example 3

N-(5-((4-(Benzyloxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)pyridin-2-yl)acrylamide[56]

To a solution of 32 (20 mg, 0.049 mmol) and Et₃N (49 mg, 0.49 mmol) inCH₂Cl₂ (0.5 mL) was added acryloyl chloride (44 mg, 0.49 mmol) and themixture was stirred for 2 h at rt. Solvent was removed under reducedpressure and the resulting residue was purified by preparatory TLC(CH₂Cl₂:MeOH—NH₃, 15:1) to afford 15.9 mg (70%) of 56. ¹H NMR (500 MHz,CDCl₃): δ 8.27 (s, 1H), 8.16 (d, J=2.2 Hz, 1H), 8.14 (d, J=8.8 Hz, 1H),8.08 (br s, 1H), 7.53 (dd, J=8.7, 2.4 Hz, 1H), 7.25-7.31 (m, 3H),7.18-7.22 (m, 2H), 6.45 (dd, J=16.9, 0.8 Hz, 1H), 6.24 (dd, J=16.9, 10.3Hz, 1H), 5.81 (dd, J=10.3, 0.8 Hz, 1H), 5.34 (s, 2H), 3.82-3.90 (m, 4H),2.42-2.50 (m, 4H), 2.35 (s, 3H); ¹³C NMR (125 MHz, CDCl₃): δ 168.3,163.8, 163.4, 161.4, 149.5, 148.0, 139.2, 136.3, 130.9, 129.4, 128.6,128.4, 128.0, 127.6, 114.1, 100.1, 68.0, 54.7, 46.1, 43.8; HRMS (ESI)m/z [M+H]⁺ calcd. for C₂₄H₂₇N₆O₂S, 463.1916; found 463.1930.

Example 4

2-Amino-N-(4-((4-(benzyloxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)phenyl)acetamide[58]

To a solution of 10 (19 mg, 0.047 mmol) in THF (1.5 mL) was addedBoc-glycine (9.1 mg, 0.052 mmol) and DCC (10.7 mg, 0.052 mmol). Afterstirring overnight at rt, THF was evaporated and 1 mL of CH₂Cl₂:TFA(4:1) was added. The solution was stirred for 45 min., then concentratedto dryness under reduced pressure to give a residue which was purifiedby preparatory TLC (CH₂Cl₂:MeOH—NH₃ (7 N), 15:1) to afford 13.5 mg (62%)of 58. ¹H NMR (500 MHz, CDCl₃): δ 9.34 (br s, 1H), 8.24 (s, 1H), 7.47(d, J=8.6 Hz, 2H), 7.24-7.30 (m, 3H), 7.15-7.21 (m, 4H), 5.35 (s, 2H),3.81-3.89 (m, 4H), 3.46 (s, 2H), 2.42-2.48 (m, 4H), 2.34 (s, 3H); ¹³CNMR (125 MHz, CDCl₃): δ 170.6, 168.4, 163.9, 161.3, 136.6, 135.9, 132.2,129.1, 128.3, 127.7, 127.4, 119.9, 101.0, 67.7, 54.8, 46.2, 45.1, 43.9;HRMS (ESI) m/z [M+H]⁺ calcd. for C₂₄H₂₉N₆O₂S, 465.2073; found 465.2076.

Example 5

2-((4-(Benzyloxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)-5-methoxyaniline[62]

A mixture of 40 (50 mg, 0.123 mmol), AcOH (50 μL) and Zn powder inCH₂Cl₂ (2 mL) was stirred at rt for 2 h. The reaction mixture wasconcentrated under reduced pressure to give a residue which was purifiedby column chromatography (CH₂Cl₂:MeOH, 9:1) to afford 44 mg (82%) of 62.¹H NMR (500 MHz, CDCl₃): δ 8.04 (s, 1H), 7.45 (m, 4H), 7.32 (m, 1H),7.30 (m, 1H), 6.22 (m, 1H), 6.17 (m, 1H), 5.36 (s, 2H), 3.87 (m, 4H),3.73 (s, 3H), 2.65 (m, 4H), 2.42 (s, 3H); ¹³C NMR (125 MHz, CDCl₃): δ167.2, 161.7, 160.5, 160.3, 149.8, 137.9, 136.4, 128.5, 128.1, 128.0,108.2, 105.0, 104.8, 100.3, 68.1, 55.2, 53.7, 44.7, 42.6; HRMS (ESI) m/z[M+H]⁺ calcd. for C₂₃H₂₈N₅O₂S, 438.1964; found 438.1963.

5-((4-(Benzyloxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)-2-methoxypyridin-3-amine[63]

To a solution of 14 (10 mg, 0.021 mmol) in 2 mL of dry dioxane was added12 mg (0.064 mmol) of sodium hydrosulfite. The resulting mixture wasstirred at rt for 1 h. The reaction was then concentrated under reducedpressure and the residue was purified by preparatory TLC(CH₂Cl₂:MeOH—NH₃ (7 N), 15:1) to yield 5.8 mg (62%) of 63. ¹H NMR (500MHz, CDCl₃) δ 8.14 (s, 1H), 7.19-7.27 (m, 7H), 6.74 (s, 1H), 6.37 (s,1H), 5.29 (s, 2H), 4.01 (s, 2H), 3.75-3.77 (m, 4H), 3.28 (s, 3H),2.37-2.39 (m, 4H), 2.26 (s, 3H); HRMS (ESI) m/z [M+H]⁺ calcd. forC₂₂H₂₇N₆O₂S, 439.1916; found 439.1909.

Example 6

Methyl2-(4-((4-(benzyloxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)phenoxy)propanoate[64]

A mixture of 37 (50 mg, 0.123 mmol), methyl 2-bromopropanoate (102 mg0.613 mmol) and K₂CO₃ in acetonitrile (1 mL) was heated at 80° C. for 1h. The reaction mixture was concentrated under reduced pressure to givea residue which was purified by preparatory TLC (CH₂Cl₂:MeOH, 20:1) toafford 42 mg (69%) of 64. ¹H NMR (500 MHz, CDCl₃): δ 8.21 (s, 1H), 7.27(m, 3H), 7.18 (m, 2H), 7.16 (d, J=8.6 Hz, 2H), 6.73 (d, J=8.6 Hz, 2H),5.36 (s, 2H), 4.70 (q, J=6.5 Hz, 1H), 3.83 (m, 4H), 3.73 (s, 3H), 2.44(m, 4H), 2.34 (s, 3H), 1.60 (d, J=6.2 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃):δ 172.5, 168.2, 163.5, 161.2, 156.4, 136.6, 130.8, 128.9, 128.3, 127.7,127.5, 115.7, 101.9, 72.8, 67.7, 54.8, 52.4, 46.2, 43.8, 18.6; HRMS(ESI) m/z [M+H]⁺ calcd. for C₂₆H₃₁N₄O₄S, 495.2066; found 495.2062.

2-(4-((4-(Benzyloxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)phenoxy)propanamide[65]

A solution of 64 (30 mg, 0.061 mmol) in 3 mL of MeOH—NH₃ (7 N) wasstirred at rt for 12 h. The reaction mixture was concentrated underreduced pressure to give a residue which was purified by preparatory TLC(CH₂Cl₂:MeOH, 10:1) to afford 26 mg (89%) of 65. ¹H NMR (500 MHz,CDCl₃): δ 8.22 (s, 1H), 7.25-7.30 (m, 3H), 7.15-7.23 (m, 4H), 6.76 (d,J=8.8 Hz, 2H), 6.32 (br s, 1H), 5.39 (br s, 1H), 5.36 (s, 2H), 4.60 (q,J=6.8 Hz, 1H), 3.80-3.87 (m, 4H), 2.43-2.48 (m, 4H), 2.34 (s, 3H), 1.57(d, J=6.8 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃): δ 174.6, 168.2, 163.6,161.3, 155.6, 136.6, 130.7, 129.7, 128.3, 127.8, 127.4, 116.0, 103.5,75.0, 67.7, 54.8, 46.2, 43.8, 18.6; HRMS (ESI) m/z [M+H]⁺ calcd. forC₂₅H₃₀N₅O₃S, 480.2069; found 480.2075.

Example 7

General Procedure for the Synthesis of 66-80.

A mixture of nitrile (1 equiv.) and KOH (25 eq.) in t-BuOH was heated at80° C. for 1 h. Solvent was removed under reduced pressure and theresidue was purified by preparatory TLC to afford the desired product.

4-((4-(Benzyloxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)benzamide[66]

66 was obtained in 83% yield following the general procedure above. ¹HNMR (500 MHz, CDCl₃): δ 8.26 (s, 1H), 7.63 (d, J=8.4 Hz, 2H), 7.22-7.26(m, 3H), 7.11-7.15 (m, 4H), 5.94 (br s, 1H), 5.56 (br s, 1H), 5.36 (s,2H), 3.85-3.92 (m, 4H), 2.44-2.50 (m, 4H), 2.36 (s, 3H); HRMS (ESI) m/z[M+H]⁺ calcd. for C₂₃H₂₆N₅O₂S, 436.1807; found 436.1801.

3-((4-(Benzyloxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)benzamide[67]

67 was obtained in 78% yield following the general procedure above. ¹HNMR (500 MHz, CDCl₃): δ 8.19 (s, 1H), 7.50 (s, 1H), 7.48 (t, J=5.5 Hz,1H), 7.15-7.18 (m, 1H), 7.06 (d, J=7.3 Hz, 1H), 7.05 (d, J=5.8 Hz, 1H),6.01 (br s, 2H), 5.27 (s, 2H), 3.77-3.79 (m, 4H), 2.37-2.39 (m, 4H),2.26 (s, 3H); ¹³C NMR (125 MHz, CDCl₃): δ 169.0, 168.5, 164.5, 161.5,138.8, 136.4, 134.1, 130.7, 129.0, 128.4, 127.9, 127.4, 126.1, 124.7,99.1, 67.8, 54.7, 46.1, 43.8; MS (m/z): 436.2 [M+H]⁺.

5-((4-(Benzyloxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)-2-fluorobenzamide[68]

68 was obtained in 76% yield following the general procedure above. ¹HNMR (500 MHz, CDCl₃): δ 8.19 (s, 1H), 7.87 (dd, J=7.2, 2.6 Hz, 1H),7.13-7.22 (m, 4H), 7.08-7.12 (m, 2H), 6.87 (dd, J=11.4, 8.7 Hz, 1H),6.51 (br s, 1H), 5.92 (br s, 1H), 5.28 (s, 2H), 3.78 (m, 4H), 2.38 (m,4H), 2.27 (s, 3H); ¹³C NMR (125 MHz, CDCl₃): δ 168.4, 164.3, 164.2,161.5, 159.3 (d, J=246 Hz), 136.4, 134.5 (d, J=2.5 Hz), 133.0 (d, J=9.1Hz), 131.2, 128.3, 127.8, 127.5, 120.5 (d, J=12.5 Hz), 116.5 (d, J=26.3Hz), 99.5, 67.8, 54.8, 46.2, 43.9. MS (m/z): 454.0 [M+H]⁺.

4-((4-(Benzyloxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)-2-(trifluoromethyl)benzamide[70]

70 was obtained in 70% yield following the general procedure above. ¹HNMR (500 MHz, CDCl₃): δ 8.18 (s, 1H), 7.36-7.39 (m, 1H), 7.31 (d, J=8.1Hz, 1H), 7.17-7.23 (m, 3H), 7.11-7.15 (m, 1H), 7.06-7.10 (m, 2H), 6.02(br s, 1H), 5.71 (br s, 1H), 5.28 (s, 2H), 3.81 (m, 4H), 2.39 (m, 4H),2.27 (s, 3H); MS (m/z): 503.9 [M+H]⁺.

6-((4-(Benzyloxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)nicotinamide[72]

72 was obtained in 84% yield following the general procedure above. ¹HNMR (500 MHz, CDCl₃): δ 8.64 (s, 1H), 8.19 (s, 1H), 7.80 (dd, J=8.4, 2.0Hz, 1H), 7.16-7.20 (m, 3H), 7.10-7.15 (m, 2H), 6.88 (d, J=8.4 Hz, 1H),5.65 (br s, 2H), 5.31 (s, 2H), 3.83 (m, 4H), 2.42 (m, 4H), 2.30 (s, 3H);MS (m/z): 437.0 [M+H]⁺.

4-((4-(Benzyloxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)-3-methylbenzamide[73]

73 was obtained in 88% yield following the general procedure above. ¹HNMR (500 MHz, CDCl₃) δ 8.23 (s, 1H), 7.58 (s, 1H), 7.38 (dd, J=8.2, 1.4Hz, 1H), 7.21-7.28 (m, 3H), 7.12-7.18 (m, 2H), 6.79 (d, J=8.2 Hz, 1H),5.94 (br s, 1H), 5.61 (br s, 1H), 5.36 (s, 2H), 3.80-4.00 (m, 4H),2.45-2.51 (m, 4H), 2.44 (s, 3H), 2.35 (s, 3H); MS (m/z): [M+H]⁺ 450.2

4-((4-(Benzyloxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)-2-methylbenzamide[74]

74 was obtained in 81% yield following the general procedure above. ¹HNMR (500 MHz, CDCl₃) δ 8.25 (s, 1H), 7.20-7.30 (m, 5H), 7.16 (d, J=6.7Hz, 2H), 6.97 (s, 1H), 6.92 (d, J=8.1 Hz, 1H), 5.65 (br s, 2H), 5.37 (s,2H), 3.87 (m, 4H), 2.48 (m, 4H), 2.41 (s, 3H), 2.35 (s, 3H); MS (m/z):[M+H]⁺ 450.0.

4-((4-(Benzyloxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)-2-bromobenzamide[77]

77 was obtained in 49% yield following the general procedure above. ¹HNMR (600 MHz, CD₂Cl₂/MeOH-d₄): δ 8.17 (s, 1H), 7.32 (d, J=8.2 Hz, 1H),7.17-7.24 (m, 4H), 7.10-7.14 (m, 2H), 7.01 (dd, J=8.1, 1.8 Hz, 1H), 5.29(s, 2H), 3.55-4.15 (m, 4H), 2.20-2.75 (m, 7H); HRMS (ESI) m/z [M+H]⁺calcd. for C₂₃H₂₄BrN₅O₂S, 514.0912; found 514.0902.

4-((4-(Benzyloxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)-2-chlorobenzamide[78]

78 was obtained in 56% yield following the general procedure above. ¹HNMR (500 MHz, CD₂Cl₂/MeOH-d₄): δ 8.16 (s, 1H), 7.41 (d, J=8.2 Hz, 1H),7.15-7.25 (m, 3H), 7.09-7.14 (m, 2H), 7.02 (s, 1H), 6.97 (d, J=8.2 Hz,1H), 5.26 (s, 2H), 3.77-3.88 (m, 4H), 2.40-2.53 (m, 4H), 2.29 (s, 3H);¹³C NMR (125 MHz, CD₂Cl₂/MeOH-d₄): δ 169.2, 169.1, 165.2, 162.0, 143.7,136.8, 131.8, 131.4, 130.5, 128.8, 128.3, 127.8, 127.5, 125.0, 98.1,68.5, 54.8, 45.7, 43.7; HRMS (ESI) m/z [M+H]⁺ calcd. for C₂₃H₂₄ClN₅O₂S,470.1417; found 470.1422.

4-((4-(Benzyloxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)-2-fluorobenzamide[79]

79 was obtained in 53% yield following the general procedure above. ¹HNMR (500 MHz, CDCl₃) δ 8.25 (s, 1H), 7.94-7.97 (m, 1H), 7.26-7.27 (m,3H), 7.17 (m, 2H), 6.96 (d, J=8.3 Hz, 1H), 6.77 (d, J=12.6 Hz, 1H), 6.57(bs, 1H), 5.89 (bs, 1H), 5.38 (s, 2H), 3.92 (m, 4H), 2.52 (m, 4H), 2.39(s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 168.8, 165.3, 164.6, 161.9, 146.9,136.4, 132.6, 128.6, 128.2, 127.7, 122.2, 116.6, 113.2, 112.9, 97.3,68.1, 54.9, 46.3, 44.0; HRMS (ESI) m/z [M+H]⁺ calcd. for C₂₃H₂₅FN₅O₂S454.1713; found 454.1713.

4-((4-(Benzyloxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)-2-iodobenzamide[80]

80 was obtained in 52% yield following the general procedure above. ¹HNMR (500 MHz, CDCl₃) δ 8.20 (s, 1H), 7.57 (s, 1H), 7.21-7.26 (m, 4H),7.13 (d, J=7.4 Hz, 2H), 7.03 (d, J=8.0 Hz, 1H), 5.70 (br s, 2H), 5.31(s, 2H), 3.91 (m, 4H), 2.55 (m, 4H), 2.37 (s, 3H); HRMS (ESI) m/z [M+H]⁺calcd. for C₂₃H₂₅IN₅O₂S 562.0774; found 562.0787.

Example 8

4-((4-(Benzyloxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)benzoicacid [81]

A mixture of 49 (100 mg, 0.222 mmol) and LiOH (27 mg, 1.11 mmol) in 3 mLof THF:H₂O (2:1) was stirred at rt for 1.5 h. The reaction mixture wasconcentrated under reduced pressure to give a residue which was purifiedby column chromatography (CH₂Cl₂:MeOH, 9:1) to afford 93 mg (96%) of 81.¹H NMR (500 MHz, CDCl₃/MeOH-d₄): δ 8.18 (s, 1H), 7.76 (d, J=8.5 Hz, 2H),7.10-7.15 (m, 3H), 6.95-7.02 (m, 4H), 5.23 (s, 2H), 3.40 (m, 4H), 2.81(m, 4H), 2.18 (s, 3H); HRMS (ESI) m/z [M+H]⁺ calcd. for C₂₃H₂₅N₄O₃S,437.1647; found 437.1654.

4-((4-(Benzyloxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)benzoylchloride [82]

To a mixture of 81 (90 mg, 0.206 mmol) in CH₂Cl₂ was added oxalylchloride (35 μL, 0.412 mmol) and the reaction mixture was stirred at rtfor 5 h. The reaction mixture was concentrated under reduced pressureand dried to afford quantitative yield of 82, which was used withoutfurther purification.

General Procedure for Synthesis of 83-84.

To a solution of 82 (1 equiv.) in CH₂Cl₂ (1 mL) was added amine (3equiv.) and was stirred for 2 h at rt. Solvent was removed under reducedpressure and the resulting residue was purified by preparatory TLC.

4-((4-(Benzyloxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)-N-methylbenzamide[83]

83 was obtained in 93% yield following the general procedure above. ¹HNMR (500 MHz, CDCl₃): δ 8.29 (s, 1H), 7.61 (d, J=8.5 Hz, 2H), 7.24-7.28(m, 3H), 7.12-7.17 (m, 4H), 6.14 (br s, 1H), 5.37 (s, 2H), 3.97 (m, 4H),3.02 (d, J=4.8 Hz, 3H), 2.61 (m, 4H), 2.45 (s, 3H); ¹³C NMR (125 MHz,CDCl₃): δ 168.7, 167.6, 164.8, 161.5, 142.5, 136.3, 131.4, 128.4, 127.8,127.4, 127.2, 126.3, 98.8, 67.9, 54.4, 45.6, 43.3, 26.8; MS (m/z): 450.2[M+H]⁺.

4-((4-(Benzyloxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)-N,N-dimethylbenzamide[84]

84 was obtained in 88% yield following the general procedure above. ¹HNMR (500 MHz, CDCl₃): δ 7.27 (s, 1H), 7.25-7.30 (m, 7H), 7.13 (d, J=6.9Hz, 2H), 5.38 (s, 2H), 3.84-3.93 (m, 4H), 3.01 (s, 3H), 2.88 (s, 3H),2.47-2.49 (m, 4H), 2.36 (s, 3H); ¹³C NMR (125 MHz, CDCl₃): δ 171.2,168.6, 164.8, 161.5, 140.2, 136.4, 133.1, 129.8, 128.3, 127.7, 127.4,126.3, 98.6, 67.8, 61.3, 54.8, 46.2, 43.8; MS (m/z): 464.0 [M+H]⁺.

Example 9

4-((4-(Benzyloxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)-N-(pyrrolidin-1-ylmethyl)benzamide[92]

To a solution of 66 (20 mg, 0.046 mmol) in t-BuOH (2 mL) was addedpyrrolidine (8.3 μL, 0.10 mmol) and formalin (10 μL, 0.134 mmol). Thereaction mixture was stirred at rt for 1 h and then refluxed for 2 h.Solvent was removed under reduced pressure and the residue was purifiedby preparatory TLC (CH₂Cl₂:MeOH—NH₃, 20:1) to afford 8.6 mg (36%) of 92.¹H NMR (500 MHz, CDCl₃) δ 8.26 (s, 1H), 7.60 (d, J=8.4 Hz, 2H),7.23-7.24 (m, 3H), 7.11-7.14 (m, 4H), 6.55 (br s, 1H), 5.35 (s, 2H),4.38 (d, J=6.0 Hz, 2H), 3.86-3.87 (m, 4H), 2.69-2.71 (m, 4H), 2.45-2.47(m, 4H), 2.35 (s, 3H), 1.79-1.80 (m, 4H); ¹³C NMR (125 MHz, CDCl₃) δ168.6, 167.0, 164.9, 161.6, 143.1, 136.4, 131.0, 128.5, 127.4, 127.2,126.3, 126.0, 98.1, 67.8, 58.8, 54.8, 51.0, 46.2, 43.9, 23.7; HRMS (ESI)m/z [M+H]⁺ calcd. for C₂₈H₃₅N₆O₂S 519.2542; found 519.2549.

4-((4-(Benzyloxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)-N-(piperidin-1-ylmethyl)benzamide[93]

To a solution of 66 (20 mg, 0.046 mmol) in t-BuOH (2 mL) was addedpiperidine (10 μL, 0.10 mmol) and formalin (10 μL, 0.134 mmol). Thereaction mixture was stirred at rt for 1 h and then refluxed for 2 h.Solvent was removed under reduced pressure and the residue was purifiedby preparatory TLC (CH₂Cl₂:MeOH—NH₃, 20:1) to afford 9.1 mg (37%) of 93.¹H NMR (500 MHz, CDCl₃) δ 8.23 (s, 1H), 7.61 (d, J=8.4 Hz, 2H),7.22-7.24 (m, 3H), 7.11-7.13 (m, 4H), 6.52 (br s, 1H), 5.36 (s, 2H),4.25 (d, J=6.2 Hz, 2H), 3.86-3.88 (m, 4H), 2.56-2.58 (m, 4H), 2.45-2.47(m, 4H), 2.35 (s, 3H), 1.57-1.62 (m, 4H), 1.44-1.45 (m, 2H); ¹³C NMR(125 MHz, CDCl₃) δ 168.6, 167.2, 164.9, 161.6, 143.1, 136.4, 130.9,128.4, 127.4, 127.2, 126.3, 126.0, 98.1, 67.6, 62.5, 54.8, 51.5, 46.2,43.9, 25.8, 24.1; HRMS (ESI) m/z [M+H]⁺ calcd. for C₂₉H₃₇N₆O₂S 533.2699;found 533.2686.

Example 10

4-(4-(4-Methoxybenzyloxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-ylthio)benzonitrile[95]

A mixture of 94 (1.0 g, 2.27 mmol) and K₂CO₃ (0.628 g, 4.54 mmol) in DMF(32 mL) was evacuated and backfilled with argon three times.Copper(I)thiophene-2-carboxylate (0.173 g, 0.908 mmol) was added andevacuated and backfilled with argon two times. 4-Mercaptobenzonitrile(0.496 g, 2.72 mmol) was added and the reaction mixture was heated at120° C. for 20 h. Solvent was removed under reduced pressure and theresidue was purified by column chromatography (CH₂Cl₂:MeOH, 200:1 to40:1) to afford 0.867 g (85%) of 95. ¹H NMR (500 MHz, CDCl₃): δ 8.22 (s,1H), 7.39 (d, J=8.3 Hz, 2H), 7.03-7.11 (m, 4H), 6.78 (d, J=8.6 Hz, 2H),5.30 (s, 2H), 3.90 (m, 4H), 3.79 (s, 3H), 2.49 (m, 4H), 2.36 (s, 3H);¹³C NMR (125 MHz, CDCl₃): δ 168.6, 165.0, 161.8, 159.5, 145.7, 132.1,129.4, 128.2, 126.1, 119.0, 113.7, 108.1, 96.9, 67.7, 55.3, 54.8, 46.2,43.9; HRMS (ESI) m/z [M+H]⁺ calcd. for C₂₄H₂₆N₅O₂S, 448.1807; found448.1823.

4-((4-((4-Methoxybenzyl)oxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)benzamide[96]

A mixture of 95 (11.2 mg, 0.025 mmol) and KOH (20 mg, 0.357 mmol) int-BuOH (500 μL) was heated at 80° C. for 1 h. Solvent was removed underreduced pressure and the residue was purified by preparatory TLC(CH₂Cl₂:MeOH—NH₃ (7 N), 20:1) to afford 9.8 mg (84%) of 96. ¹H NMR (500MHz, CDCl₃/MeOH-d₄): δ 8.19 (s, 1H), 7.56 (d, J=8.5 Hz, 2H), 6.97-7.06(m, 4H), 6.72 (d, J=8.6 Hz, 2H), 5.24 (s, 2H), 3.80-3.88 (m, 4H), 3.73(s, 3H), 2.41-2.49 (m, 4H), 2.32 (s, 3H); ¹³C NMR (125 MHz, CDCl₃): δ169.5, 168.8, 164.9, 161.7, 159.5, 143.7, 130.0, 129.5, 128.5, 127.9,126.2, 113.9, 98.5, 67.8, 55.4, 54.9, 46.2, 43.9; HRMS (ESI) m/z [M+H]⁺calcd. for C₂₄H₂₈N₅O₃S, 466.1913; found 466.1924.

4-((4-Hydroxy-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)benzonitrile[97]

To a solution of 95 (0.800 g, 1.79 mmol) in CH₂Cl₂ (4 mL) was added TFA(4 mL) dropwise over 5 minutes and stirred at rt for 12 h. The reactionmixture was concentrated under reduced pressure to give a residue whichwas purified by column chromatography (CH₂Cl₂:MeOH, 10:1 to 7:1) toafford 0.546 g (93%) of 97. ¹H NMR (500 MHz, CDCl₃/MeOH-d₄): δ 8.10 (s,1H), 7.49 (d, J=8.5 Hz, 2H), 7.22 (d, J=8.5 Hz, 2H), 3.68-3.79 (m, 4H),2.42-2.51 (m, 4H), 2.35 (s, 3H); ¹³C NMR (125 MHz, CDCl₃): δ 155.5,145.8, 132.3, 131.2, 129.0, 126.0, 119.0, 108.1, 101.7, 54.3, 45.8,44.4; HRMS (ESI) m/z [M+H]⁺ calcd. for C₁₆H₁₈N₅OS, 328.1232; found328.1234.

4-((4-Chloro-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)benzonitrile[98]

97 (0.419 g, 1.28 mmol) and POCl₃ (2 mL) were heated at 75° C. for 1 h.After cooling to rt, the reaction mixture was added to a beakercontaining ice chips. Following complete quenching of POCl₃, solidNa₂CO₃ was carefully added until pH˜9. This was transferred to aseperatory funnel and extracted with CH₂Cl₂ (4×50 mL), dried over MgSO₄,filtered and concentrated to a solid which was purified by columnchromatography (CH₂Cl₂:MeOH, 50:1 to 40:1) to afford 0.426 g (86%) of98. ¹H NMR (500 MHz, CDCl₃): δ 8.38 (s, 1H), 7.51 (d, J=8.5 Hz, 2H),7.13 (d, J=8.4 Hz, 2H), 3.85-3.94 (m, 4H), 2.43-2.51 (m, 4H), 2.36 (s,3H); MS (m/z): [M+H]⁺ 346.0/348.0.

General Procedure for Synthesis of 99a-j, m-o and q-x.

To alcohol (4.25 equiv.) dissolved in CH₃CN was added NaH (4 equiv.) andthe resulting suspension was stirred for 10 min. at rt. Then 98 (1equiv.) was added and the reaction mixture was stirred at rt for 3 h.Solvent was removed under reduced pressure and the residue was purifiedby column chromatography to afford the desired product.

4-((4-((3-(Dimethylamino)benzyl)oxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)benzonitrile[99a]

99a was obtained contaminated with unreacted alcohol following thegeneral procedure above. MS (m/z): [M+H]⁺ 461.2.

4-((2-(4-Methylpiperazin-1-yl)-4-((3-(pyrrolidin-1-yl)benzyl)oxy)pyrimidin-5-yl)thio)benzonitrile[99b]

99b was obtained in 89% yield following the general procedure above. ¹HNMR (500 MHz, CDCl₃): δ 8.20 (s, 1H), 7.36 (d, J=8.4 Hz, 2H), 7.08 (t,J=7.8 Hz, 1H), 7.05 (d, J=8.4 Hz, 2H), 6.41-6.46 (m, 2H), 6.35 (br s,1H), 5.31 (s, 2H), 3.81-3.95 (m, 4H), 3.06-3.13 (m, 4H), 2.43-2.48 (m,4H), 2.34 (s, 3H), 1.91-2.00 (m, 4H); MS (m/z): [M+H]⁺ 487.2.

4-((4-((3-(Dimethylamino)-4-fluorobenzyl)oxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)benzonitrile[99c]

99c was obtained contaminated with unreacted alcohol following thegeneral procedure above. MS (m/z): [M+H]⁺ 479.2.

4-((4-(1-(3-(Dimethylamino)phenyl)ethoxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)benzonitrile[99d]

99d was obtained contaminated with unreacted alcohol following thegeneral procedure above. MS (m/z): [M+H]⁺ 475.1.

4-((4-((3-(Cyclopropylamino)benzyl)oxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)benzonitrile[99e]

99e was obtained contaminated with unreacted alcohol following thegeneral procedure above. MS (m/z): [M+H]⁺ 473.3.

4-((4-((3-(1H-Pyrazol-1-yl)benzyl)oxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)benzonitrile[99f]

99f was obtained in 98% yield following the general procedure above. ¹HNMR (500 MHz, CDCl₃): δ 8.24 (s, 1H), 7.77 (d, J=2.5 Hz, 1H), 7.73 (d,J=1.6 Hz, 1H), 7.58-7.60 (m, 1H), 7.54-7.57 (m, 1H), 7.38 (d, J=8.5 Hz,2H), 7.34 (t, J=7.9 Hz, 1H), 7.05-7.12 (m, 3H), 6.49 (t, J=2.2 Hz, 1H),5.41 (s, 2H), 3.84-3.92 (m, 4H), 2.42-2.48 (m, 4H), 2.34 (s, 3H); MS(m/z): [M+H]⁺ 484.3.

4-((4-((3-Methoxybenzyl)oxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)benzonitrile[99g]

99g was obtained contaminated with unreacted alcohol following thegeneral procedure above. MS (m/z): [M+H]⁺ 448.3.

4-((2-(4-Methylpiperazin-1-yl)-4-phenethoxypyrimidin-5-yl)thio)benzonitrile[99h]

99h was obtained in 89% yield following the general procedure above. ¹HNMR (500 MHz, CDCl₃): δ 8.14 (s, 1H), 7.33 (d, J=8.3 Hz, 2H), 7.06-7.12(m, 3H), 6.99-7.03 (m, 2H), 6.97 (d, J=8.4 Hz, 2H), 4.43 (t, J=6.8 Hz,2H), 3.76-3.84 (m, 4H), 2.87 (t, J=6.8 Hz, 2H), 2.37-2.44 (m, 4H), 2.29(s, 3H); MS (m/z): [M+H]⁺ 432.2.

4-((4-(Furan-2-ylmethoxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)benzonitrile[99i]

99i was obtained in 96% yield following the general procedure above. ¹HNMR (500 MHz, CDCl₃): δ 8.16 (s, 1H), 7.33 (d, J=8.6 Hz, 2H), 7.26 (s,1H), 6.97 (d, J=8.6 Hz, 2H), 6.21-6.27 (m, 1H), 6.20 (d, J=3.1 Hz, 1H),5.27 (s, 2H), 3.79-3.90 (m, 4H), 2.37-2.46 (m, 4H), 2.30 (s, 3H); MS(m/z): [M+H]⁺ 408.2.

4-((4-(Furan-3-ylmethoxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)benzonitrile[99j]

99j was obtained in 76% yield following the general procedure above. ¹HNMR (500 MHz, CDCl₃): δ 8.17 (s, 1H), 7.35 (d, J=8.6 Hz, 2H), 7.22-7.28(m, 2H), 7.00 (d, J=8.6 Hz, 2H), 6.12 (s, 1H), 5.18 (s, 2H), 3.78-3.88(m, 4H), 2.37-2.48 (m, 4H), 2.30 (s, 3H); MS (m/z): [M+H]⁺ 408.2.

4-((4-((4-Fluorobenzyl)oxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)benzonitrile[99m]

99m was obtained in 70% yield following the general procedure above. ¹HNMR (500 MHz, CDCl₃): δ 8.17 (s, 1H), 7.35 (d, J=8.4 Hz, 2H), 7.04-7.07(m, 4H), 7.01 (d, J=8.4 Hz, 2H), 6.86-6.88 (m, 2H), 5.24 (s, 2H),3.81-3.85 (m, 4H), 2.40-2.45 (m, 4H), 2.30 (s, 3H); ¹³C NMR (125 MHz,CDCl₃): δ 168.5, 165.2, 161.7, 145.6, 132.1, 129.4, 129.3, 126.0, 118.9,115.4, 115.2, 108.3, 96.8, 67.2, 54.7, 46.1, 43.8; MS (m/z): [M+H]⁺436.0.

(S)-4-((4-(1-(4-Fluorophenyl)ethoxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)benzonitrile[99n]

99n was obtained in 55% yield following the general procedure above. ¹HNMR (500 MHz, CDCl₃): δ 8.14 (s, 1H), 7.37 (d, J=8.2 Hz, 2H), 7.02-7.07(m, 4H), 6.83-6.87 (m, 2H), 6.01-6.02 (m, 1H), 3.73-3.79 (m, 4H),2.36-2.40 (m, 4H), 2.26 (s, 3H), 1.40 (d, J=6.5 Hz, 3H); ¹³C NMR (125MHz, CDCl₃): δ 168.0, 164.9, 161.7, 145.8, 137.9, 132.1, 127.4, 126.2,118.9, 115.3, 115.1, 108.2, 97.0, 73.6, 54.7, 46.2, 43.9, 22.7; MS(m/z): [M+H]⁺ 450.1.

(R)-4-((4-(1-(4-Fluorophenyl)ethoxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)benzonitrile[99o]

99o was obtained in 52% yield following the general procedure above. ¹HNMR (500 MHz, CDCl₃): δ 8.14 (s, 1H), 7.37 (d, J=8.3 Hz, 2H), 7.02-7.05(m, 4H), 6.83-6.87 (m, 2H), 5.99-6.02 (m, 1H), 3.73-3.79 (m, 4H),2.36-2.39 (m, 4H), 2.27 (s, 3H), 1.39 (d, J=6.5 Hz, 3H); ¹³C NMR (125MHz, CDCl₃): δ 168.0, 164.9, 161.7, 143.8, 137.9, 132.1, 127.5, 126.2,118.9, 115.3, 115.1, 108.2, 97.0, 73.7, 54.7, 46.2, 43.9, 22.7; MS(m/z): [M+H]⁺ 450.1.

4-((4-((3-Acetylbenzyl)oxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)benzonitrile[99q]

99q was obtained contaminated with unreacted alcohol following thegeneral procedure above. MS (m/z): [M+H]⁺ 460.2.

4-((4-((2-Aminopyridin-4-yl)methoxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)benzonitrile[99r]

99r was obtained contaminated with unreacted alcohol following thegeneral procedure above. MS (m/z): [M+H]⁺ 434.2.

4-((4-((3-Iodobenzyl)oxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)benzonitrile[99s]

99s was obtained in 92% yield following the general procedure above. MS(m/z): [M+H]⁺ 444.2.

4-((4-(Benzyloxy-d₅)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)benzonitrile[99t]

99t was obtained in 82% yield following the general procedure above. MS(ESI) m/z [M+H]⁺ 423.4.

4-((4-(Benzyloxy-d₂)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)benzonitrile[99u]. 99u was obtained in 78% yield following the general procedureabove. MS (ESI) m/z [M+H]⁺ 420.4.

4-((4-((4-Iodobenzyl)oxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)benzonitrile[99v]. 99v was obtained in 72% yield following the general procedureabove. MS (ESI) m/z [M+H]⁺ 544.2.

3-(((5-((4-Cyanophenyl)thio)-2-(4-methylpiperazin-1-yl)pyrimidin-4-yl)oxy)methyl)benzonitrile[99w]. 99w was obtained in 63% yield following the general procedureabove. MS (ESI) m/z [M+H]⁺ 443.2.

4-((4-((3-Aminobenzyl)oxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)benzonitrile[99x]

99x was obtained in 96% yield following the general procedure above. ¹HNMR (500 MHz, CDCl₃): δ 8.16 (s, 1H), 7.35 (d, J=8.5 Hz, 2H), 7.02 (d,J=8.5 Hz, 2H), 6.96 (t, J=7.8 Hz, 1H), 6.50 (dd, J=7.9, 2.2 Hz, 1H),6.47 (d, J=7.6 Hz, 1H), 6.33 (s, 1H), 5.20 (s, 2H), 3.82-3.85 (m, 4H),3.51 (br s, 2H), 2.42-2.45 (m, 4H), 2.30 (s, 3H); MS (ESI) m/z [M+H]⁺433.1.

General Procedure for the Synthesis of 100a-j, m-o and q-x.

A mixture of nitrile (1 equiv.) and KOH (25 equiv.) in t-BuOH was heatedat 80° C. for 1 h. Solvent was removed under reduced pressure and theresidue was purified by preparatory TLC to afford amide.

4-((4-((3-(Dimethylamino)benzyl)oxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)benzamide4-((4-((3-(dimethylamino)benzyl)oxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)benzamide[100a]. 100a was obtained in 94% yield following the general procedureabove. ¹H NMR (500 MHz, CDCl₃): δ 8.23 (s, 1H), 7.57 (d, J=8.5 Hz, 2H),7.00-7.12 (m, 3H), 6.46-6.62 (m, 3H), 5.97 (br s, 1H), 5.64 (br s, 1H),5.32 (s, 2H), 3.82-3.91 (m, 4H), 2.79 (m, 6H), 2.41-2.50 (m, 4H), 2.34(s, 3H); ¹³C NMR (125 MHz, CDCl₃): δ 168.9, 168.7, 165.0, 161.7, 150.6,143.8, 137.1, 129.7, 129.0, 127.7, 125.7, 115.8, 112.1, 111.7, 97.7,68.3, 54.8, 46.2, 43.9, 40.5; HRMS (ESI) m/z [M+H]⁺ calcd. forC₂₅H₃₁N₆O₂S, 479.2229; found 479.2234.

4-((2-(4-Methylpiperazin-1-yl)-4-((3-(pyrrolidin-1-yl)benzyl)oxy)pyrimidin-5-yl)thio)benzamide[100b]

100b was obtained in 92% yield following the general procedure above. ¹HNMR (500 MHz, CDCl₃): δ 8.23 (s, 1H), 7.58 (d, J=8.3 Hz, 2H), 7.04-7.10(m, 3H), 6.45 (d, J=7.4 Hz, 1H), 6.41 (d, J=8.2 Hz, 1H), 6.39 (br s,1H), 5.93 (br s, 1H), 5.60 (br s, 1H), 5.31 (s, 2H), 3.84-3.91 (m, 4H),3.03-3.12 (m, 4H), 2.42-2.49 (m, 4H), 2.34 (s, 3H), 1.87-1.94 (m, 4H);¹³C NMR (125 MHz, CDCl₃): δ 168.9, 168.6, 165.0, 161.8, 148.0, 143.9,137.2, 129.6, 129.0, 128.0, 125.7, 114.5, 111.2, 110.6, 97.7, 68.4,54.8, 47.5, 46.2, 43.9, 25.4; HRMS (ESI) m/z [M+H]⁺ calcd. forC₂₇H₃₃N₆O₂S, 505.2386; found 505.2362.

4-((4-((3-(Dimethylamino)-4-fluorobenzyl)oxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)benzamide[100c]

100c was obtained in 77% yield following the general procedure above. ¹HNMR (500 MHz, CDCl₃): δ 8.23 (s, 1H), 7.56 (d, J=8.5 Hz, 2H), 7.02 (d,J=8.5 Hz, 2H), 6.82-6.88 (m, 1H), 6.71 (dd, J=8.6, 2.0 Hz, 1H),6.61-6.67 (m, 1H), 6.10 (br s, 1H), 5.77 (br s, 1H), 5.27 (s, 2H),3.82-3.92 (m, 4H), 2.67 (s, 6H), 2.42-2.50 (m, 4H), 2.34 (s, 3H); ¹³CNMR (125 MHz, CDCl₃): δ 168.8, 168.7, 165.1, 161.7, 154.6 (d, J=245 Hz),143.6, 140.5 (d, J=9.0 Hz), 132.4 (d, J=3.6 Hz), 129.9, 127.7, 125.6,120.3 (d, J=8.4 Hz), 117.8 (d, J=3.7 Hz), 115.9 (d, J=21.5 Hz), 97.7,67.5, 54.8, 46.2, 43.9, 42.6 (d, J=3.8 Hz); HRMS (ESI) m/z [M+H]⁺ calcd.for C₂₅H₃₀FN₆O₂S, 497.2135; found 497.2152.

4-((4-(1-(3-(Dimethylamino)phenyl)ethoxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)benzamide[100d]

100d was obtained in 85% yield following the general procedure above. ¹HNMR (600 MHz, CDCl₃): δ 8.20 (s, 1H), 7.59 (d, J=8.4 Hz, 2H), 7.05-7.11(m, 3H), 6.54-6.58 (m, 2H), 6.48 (d, J=7.4 Hz, 1H), 6.05 (q, J=6.5 Hz,1H), 6.04 (br s, 1H), 5.72 (br s, 1H), 3.75-3.87 (m, 4H), 2.81 (s, 6H),2.38-2.47 (m, 4H), 2.32 (s, 3H), 1.48 (d, J=6.5 Hz, 3H); ¹³C NMR (150MHz, CDCl₃): δ 168.8, 168.4, 164.8, 161.7, 150.5, 144.0, 143.2, 130.0,129.0, 128.0, 126.0, 114.2, 111.8, 110.0, 98.1, 74.8, 54.8, 46.2, 43.8,40.5, 22.9; HRMS (ESI) m/z [M+H]⁺ calcd. for C₂₆H₃₃N₆O₂S, 493.2386;found 493.2394.

4-((4-((3-(Cyclopropylamino)benzyl)oxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)benzamide[100e]

100e was obtained in 75% yield following the general procedure above. ¹HNMR (600 MHz, CDCl₃): δ 8.23 (s, 1H), 7.59 (d, J=8.5 Hz, 2H), 7.10 (d,J=8.5 Hz, 2H), 7.04 (t, J=7.8 Hz, 1H), 6.66 (dd, J=8.0, 1.7 Hz, 1H),6.52 (d, J=7.5 Hz, 1H), 6.46 (s, 1H), 6.00 (br s, 1H), 5.60 (br s, 1H),5.27 (s, 2H), 4.06 (br s, 1H), 3.80-3.93 (m, 4H), 2.43-2.50 (m, 4H),2.34 (s, 3H), 2.25-2.30 (m, 1H), 0.62-0.67 (m, 2H), 0.41-0.45 (m, 2H);¹³C NMR (150 MHz, CDCl₃): δ 168.75, 168.72, 164.9, 161.7, 148.8, 143.8,137.3, 129.8, 129.0, 127.7, 126.0, 116.8, 112.5, 112.2, 97.9, 68.0,54.8, 46.2, 43.8, 25.2, 7.4; HRMS (ESI) m/z [M+H]⁺ calcd. forC₂₆H₃₁N₆O₂S, 491.2229; found 491.2243.

4-((4-((3-(1H-Pyrazol-1-yl)benzyl)oxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)benzamide[100f]

100f was obtained in 70% yield following the general procedure above. ¹HNMR (500 MHz, CDCl₃): δ 8.27 (s, 1H), 7.73 (d, J=2.5 Hz, 1H), 7.70 (d,J=1.7 Hz, 1H), 7.53-7.59 (m, 4H), 7.32 (t, J=7.8 Hz, 1H), 7.10 (t, J=8.4Hz, 2H), 7.06 (t, J=7.7 Hz, 1H), 6.45 (t, J=2.2 Hz, 1H), 6.07 (br s,1H), 5.65 (br s, 1H), 5.41 (s, 2H), 3.84-3.93 (m, 4H), 2.43-2.50 (m,4H), 2.34 (s, 3H); ¹³C NMR (125 MHz, CDCl₃): δ 168.7, 168.5, 165.0,161.6, 143.4, 141.2, 140.2, 138.0, 130.0, 129.5, 127.8, 126.9, 125.9,125.4, 118.7, 118.3, 107.8, 97.9, 67.3, 54.7, 46.1, 43.9; HRMS (ESI) m/z[M+H]⁺ calcd. for C₂₆H₂₈N₇O₂S, 502.2025; found 502.2022.

4-((4-((3-Methoxybenzyl)oxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)benzamide[100g]

100g was obtained in 60% yield following the general procedure above. ¹HNMR (600 MHz, CDCl₃): δ 8.26 (s, 1H), 7.61 (d, J=8.3 Hz, 2H), 7.16 (t,J=7.8 Hz, 1H), 7.10 (d, J=8.2 Hz, 2H), 6.78 (d, J=8.2 Hz, 1H), 6.75 (d,J=7.5 Hz, 1H), 6.67 (s, 1H), 6.06 (br s, 1H), 5.65 (br s, 1H), 5.33 (s,2H), 3.86-3.92 (m, 4H), 3.68 (s, 3H), 2.46-2.51 (m, 4H), 2.36 (s, 3H);¹³C NMR (150 MHz, CDCl₃): δ 168.8, 168.6, 165.0, 161.7, 160.0, 143.6,137.9, 129.9, 129.4, 127.8, 125.9, 119.8, 113.3, 113.2, 97.9, 67.7,55.2, 54.8, 46.2, 43.9; HRMS (ESI) m/z [M+H]⁺ calcd. for C₂₄H₂₈N₅O₃S,466.1913; found 466.1904.

4-((2-(4-Methylpiperazin-1-yl)-4-phenethoxypyrimidin-5-yl)thio)benzamide[100h]

100h was obtained in 99% yield following the general procedure above. ¹HNMR (500 MHz, CDCl₃): δ 8.22 (s, 1H), 7.60 (d, J=8.7 Hz, 2H), 7.11-7.17(m, 3H), 7.02-7.10 (m, 4H), 5.95 (br s, 1H), 5.72 (br s, 1H), 4.47 (t,J=7.0 Hz, 2H), 3.80-3.89 (m, 4H), 2.91 (t, J=7.0 Hz, 2H), 2.40-2.50 (m,4H), 2.34 (s, 3H); ¹³C NMR (125 MHz, CDCl₃): δ 169.2, 168.9, 165.2,162.0, 144.0, 138.1, 130.0, 129.2, 128.6, 127.9, 126.6, 125.8, 97.7,67.4, 55.0, 46.4, 44.0, 35.3; HRMS (ESI) m/z [M+H]⁺ calcd. forC₂₄H₂₈N₅O₂S, 450.1964; found 450.1951.

4-((4-(Furan-2-ylmethoxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)benzamide[100i]

100i was obtained in 76% yield following the general procedure above. ¹HNMR (500 MHz, CDCl₃): δ 8.23 (s, 1H), 7.57 (d, J=8.4 Hz, 2H), 7.30 (s,1H), 7.05 (d, J=8.4 Hz, 2H), 6.26-6.29 (m, 1H), 6.24 (d, J=3.2 Hz, 1H),5.94 (br s, 1H), 5.62 (br s, 1H), 5.31 (s, 2H), 3.84-3.93 (m, 4H),2.43-2.52 (m, 4H), 2.35 (s, 3H); ¹³C NMR (125 MHz, CDCl₃): δ 168.9,168.7, 165.3, 161.7, 150.0, 143.7, 143.1, 130.0, 127.9, 126.2, 110.6,110.4, 98.2, 60.1, 55.0, 46.4, 44.1; HRMS (ESI) m/z [M+H]⁺ calcd. forC₂₁H₂₄N₅O₃S, 426.1600; found 426.1598.

4-((4-(Furan-3-ylmethoxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)benzamide[100j]

100j was obtained in 82% yield following the general procedure above. ¹HNMR (500 MHz, CDCl₃/MeOH-d₄): δ 8.17 (s, 1H), 7.57 (d, J=8.5 Hz, 2H),7.18-7.26 (m, 2H), 7.02 (d, J=8.5 Hz, 2H), 6.12 (br s, 1H), 5.17 (s,2H), 3.78-3.87 (m, 4H), 2.42-2.49 (m, 4H), 2.31 (s, 3H); ¹³C NMR (125MHz, CDCl₃): δ 169.8, 168.7, 164.9, 161.6, 143.5, 143.3, 141.1, 129.9,127.9, 126.0, 120.7, 110.3, 98.4, 60.0, 54.8, 46.0, 43.7; HRMS (ESI) m/z[M+H]⁺ calcd. for C₂₁H₂₄N₅O₃S, 426.1600; found 426.1596.

4-((4-((4-Fluorobenzyl)oxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)benzamide[100m]

100m was obtained in 85% yield following the general procedure above. ¹HNMR (500 MHz, CDCl₃): δ 8.19 (s, 1H), 7.55 (d, J=8.4 Hz, 2H), 7.01-7.05(m, 4H), 6.80-6.88 (m, 2H), 5.92 (br s, 1H), 5.70 (br s, 1H), 5.24 (s,2H), 3.80-3.85 (m, 4H), 2.40-2.43 (m, 4H), 2.29 (s, 3H); ¹³C NMR (125MHz, CDCl₃): δ 168.6, 168.5, 164.9, 161.6, 143.6, 132.1, 129.9, 129.3,127.7, 126.0, 115.3, 115.2, 98.0, 67.1, 54.8, 46.2, 43.9; MS (m/z):[M+H]⁺ 454.1.

(S)-4-((4-(1-(4-Fluorophenyl)ethoxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)benzamide[100n]

100n was obtained in 83% yield following the general procedure above. ¹HNMR (600 MHz, CDCl₃): δ 8.16 (s, 1H), 7.57 (d, J=8.5 Hz, 2H), 7.06 (d,J=8.5 Hz, 2H), 6.99-7.02 (m, 2H), 6.81-6.85 (m, 2H), 5.98-6.02 (m, 1H),3.68-3.79 (m, 4H), 2.37-2.39 (m, 4H), 2.27 (s, 3H), 1.39 (d, J=6.6 Hz,3H); ¹³C NMR (150 MHz, CDCl₃): δ 168.7, 168.0, 164.7, 161.6, 143.8,138.0, 129.9, 127.7, 127.5, 126.2, 115.2, 115.1, 98.2, 73.6, 54.7, 46.2,43.8, 22.8; MS (m/z): [M+H]⁺ 468.2.

(R)-4-((4-(1-(4-Fluorophenyl)ethoxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)benzamide[100o]

100o was obtained in 78% yield following the general procedure above. ¹HNMR (600 MHz, CDCl₃): δ 8.16 (s, 1H), 7.57 (d, J=8.5 Hz, 2H), 7.06 (d,J=8.5 Hz, 2H), 6.99-7.02 (m, 2H), 6.81-6.85 (m, 2H), 5.98-6.02 (m, 1H),3.72-3.79 (m, 4H), 2.37-2.40 (m, 4H), 2.27 (s, 3H), 1.39 (d, J=6.6 Hz,3H); ¹³C NMR (150 MHz, CDCl₃): δ 168.7, 168.0, 164.7, 161.5, 143.8,138.0, 129.9, 127.7, 127.4, 126.2, 115.2, 115.0, 98.3, 73.6, 54.7, 46.2,43.8, 22.8; MS (m/z): [M+H]⁺ 468.2.

4-((4-((3-Acetylbenzyl)oxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)benzamide[100q]

100q was obtained in 55% yield following the general procedure above. ¹HNMR (600 MHz, CDCl₃): δ 8.28 (s, 1H), 7.81-7.83 (m, 1H), 7.78 (s, 1H),7.63-7.67 (m, 2H), 7.37 (d, J=5.0 Hz, 2H), 7.09-7.13 (m, 2H), 6.43 (brs, 1H), 5.54 (br s, 1H), 5.39 (s, 2H), 3.89 (m, 4H), 2.54 (s, 3H), 2.51(m, 4H), 2.38 (s, 3H); HRMS (ESI) m/z [M+H]⁺ calcd. for C₂₅H₂₇N₅O₃S,478.1913; found 478.1911.

4-((4-((2-Aminopyridin-4-yl)methoxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)benzamide[100r]

100r was obtained in 48% yield following the general procedure above. ¹HNMR (600 MHz, CDCl₃/MeOH-d₄): δ 8.29 (s, 1H), 7.89 (d, J=5.3 Hz, 1H),7.67 (d, J=8.3 Hz, 2H), 7.17 (d, J=8.5 Hz, 2H), 6.42 (d, J=5.2, 1H),5.94 (s, 1H), 5.23 (s, 2H), 3.86 (m, 4H), 2.48 (m, 4H), 2.36 (s, 3H);¹³C NMR (150 MHz, CDCl₃/MeOH-d₄): δ 169.3, 168.2, 164.9, 161.7, 158.7,147.8, 147.6, 143.6, 130.4, 127.9, 126.5, 112.1, 98.2, 66.2, 54.9, 46.3,43.9; HRMS (ESI) m/z [M+H]⁺ calcd. for C₂₂H₂₆N₇O₂S, 452.1869; found452.1860.

4-((4-((3-Iodobenzyl)oxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)benzamide[100s]

100s was obtained in 35% yield following the general procedure above. ¹HNMR (500 MHz, CDCl₃) δ 8.27 (s, 1H), 7.66 (d, J=8.3 Hz, 2H), 7.57 (d,J=7.8 Hz, 1H), 7.52 (s, 1H), 7.13 (d, J=8.3 Hz, 2H), 7.08 (d, J=7.6 Hz,1H), 6.98 (t, J=7.8 Hz, 1H), 6.02 (br s, 1H), 5.67 (br s, 1H), 5.28 (s,2H), 3.86-3.88 (m, 4H), 2.47-2.49 (m, 4H), 2.36 (s, 3H); ¹³C NMR (150MHz, CDCl₃) δ 168.7, 168.3, 165.0, 161.6, 143.4, 138.7, 136.9, 136.3,130.1, 130.0, 127.9, 126.6, 125.9, 97.8, 94.2, 66.8, 54.8, 46.2, 43.9;HRMS (ESI) m/z [M+H]⁺ calcd. for C₂₃H₂₅IN₅O₂S 562.0774; found 562.0758.

4-((4-(Benzyloxy-d₅)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)benzamide[100t]

100t was obtained in 67% yield following the general procedure above. ¹HNMR (600 MHz, CDCl₃) δ 8.26 (s, 1H), 7.62 (d, J=8.4 Hz, 1H), 7.12 (d,J=8.4 Hz, 2H), 6.02 (br s, 1H), 5.73 (br s, 1H), 5.36 (s, 2H), 3.87-3.89(m, 4H), 2.46-2.48 (m, 4H), 2.35 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ168.7, 168.6, 164.9, 161.6, 143.7, 136.2, 129.8, 127.8, 127.7, 127.3,127.0, 126.0, 97.9, 67.7, 54.8, 46.2, 43.9; HRMS (ESI) m/z [M+H]⁺ calcd.for C₂₃H₂₁D₅N₅O₂S 441.2121; found 441.2122.

4-((4-(Benzyloxy-d₂)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)benzamide[100u]

100u was obtained in 77% yield following the general procedure above. ¹HNMR (600 MHz, CDCl₃) δ 8.26 (s, 1H), 7.62 (d, J=8.3 Hz, 2H), 7.24-7.25(m, 3H), 7.11-7.14 (m, 4H), 6.03 (br s, 1H), 5.76 (br s, 1H), 3.86-3.88(m, 4H), 2.46-2.48 (m, 4H), 2.35 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ168.7, 168.6, 164.9, 161.6, 143.7, 136.2, 129.8, 128.3, 127.9, 127.7,127.5, 126.0, 97.9, 67.6, 54.8, 46.2, 43.9; HRMS (ESI) m/z [M+H]⁺ calcd.for C₂₃H₂₄D₂N₅O₂S 438.1933; found 438.1928.

4-((4-((4-Iodobenzyl)oxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)benzamide[100v]

100v was obtained in 68% yield following the general procedure above. ¹HNMR (600 MHz, CDCl₃/MeOD-d₄) δ 8.24 (s, 1H), 7.63 (d, J=8.4 Hz, 2H),7.54 (d, J=8.2 Hz, 2H), 7.08 (d, J=8.4 Hz, 2H), 6.84 (d, J=8.2 Hz, 2H),5.26 (s, 2H), 3.87 (s, 4H), 2.51 (s, 4H), 2.20 (s, 3H); ¹³C NMR (150MHz, CDCl₃/MeOD-d₄) δ 169.2, 168.4, 164.9, 161.4, 143.4, 137.4, 136.0,129.9, 129.2, 127.8, 126.0, 93.4, 67.2, 54.5, 45.9, 43.5; HRMS (ESI) m/z[M+H]⁺ calcd. for C₂₃H₂₅IN₅O₂S 562.0774; found 562.0797.

3-(((5-((4-Carbamoylphenyl)thio)-2-(4-methylpiperazin-1-yl)pyrimidin-4-yl)oxy)methyl)benzamide[100w]

100w was obtained in 53% yield following the general procedure above. ¹HNMR (600 MHz, CDCl₃/MeOH-d₄) δ 8.24 (s, 1H), 7.63-7.69 (m, 4H),7.25-7.29 (m, 2H), 7.05 (d, J=8.5 Hz, 2H), 5.36 (s, 2H), 3.96 (m, 4H),2.79 (m, 4H), 2.55 (s, 3H); HRMS (ESI) m/z [M+H]⁺ calcd. for C₂₄H₂₇N₆O₃S479.1865; found 479.1855.

4-((4-((3-Aminobenzyl)oxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)benzamide[100x]

100x was obtained in 64% yield following the general procedure above. ¹HNMR (600 MHz, CDCl₃/MeOD-d₄) δ 8.25 (s, 1H), 7.63 (d, J=8.5 Hz, 2H),7.10 (d, J=8.5 Hz, 2H), 7.01 (t, J=7.7 Hz, 1H), 6.53-6.57 (m, 2H), 6.22(s, 1H), 5.24 (s, 2H), 3.91 (m, 4H), 2.55 (m, 4H), 2.39 (s, 3H); ¹³C NMR(150 MHz, CDCl₃/MeOD-d₄) δ 169.6, 168.7, 164.7, 161.6, 146.5, 143.5,137.5, 130.2, 129.3, 127.9, 126.3, 118.0, 115.0, 114.2, 98.6, 68.0,54.7, 45.9, 43.6; HRMS (ESI) m/z [M+H]⁺ calcd. for C₂₃H₂₇N₆O₂S 451.1916;found 451.1908.

Example 11

4-((4-((3-Azidobenzyl)oxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)benzamide[101]

To a solution of 100x (20 mg, 0.044 mmol) and p-TsOH (22 mg, 0.131 mmol)in CH₃CN (1 mL) and H₂O (2 drops) was added NaNO₂ (8 mg, 0.118 mmol) andNaN₃ (15 mg, 0.231) and was stirred at rt for 4 h. The reaction mixturewas concentrated to dryness under reduced pressure to give a residuewhich was purified by preparatory TLC (CH₂Cl₂:MeOH—NH₃ (7 N), 15:1) toafford 5.5 mg (26%) of 101. ¹H NMR (600 MHz, CDCl₃) δ 8.29 (s, 1H), 7.65(d, J=8.5 Hz, 2H), 7.24 (t, J=7.9 Hz, 1H), 7.12 (d, J=8.6 Hz, 2H),6.91-6.94 (m, 2H), 6.80 (s, 1H), 6.04 (br s, 1H), 5.64 (br s, 1H), 5.24(s, 2H), 4.00 (m, 4H), 2.70 (m, 4H), 2.49 (s, 3H); ¹³C NMR (150 MHz,CDCl₃) δ 168.8, 168.7, 165.2, 161.6, 143.4, 140.4, 138.5, 130.3, 130.0,128.1, 126.2, 124.0, 118.7, 118.1, 98.9, 67.5, 54.6, 53.7, 43.3; HRMS(ESI) m/z [M+H]⁺ calcd. for C₂₃H₂₅N₈O₂S 477.1821; found 477.1811.

Example 12

4-((4-(Benzylamino)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)benzamide[102]

A mixture of 98 (20 mg, 0.058 mmol) and benzylamine (18.6 mg, 0.174mmol) in acetonitrile (500 μL) was heated at 80° C. for 2 h. Solvent wasremoved under reduced pressure and the residue was purified bypreparatory TLC (CH₂Cl₂:MeOH—NH₃ (7 N), 20:1) to afford a residue. Tothis was added t-BuOH (650 μL) and KOH (81 mg, 1.45 mmol) and themixture heated at 80° C. for 1 h. Solvent was removed under reducedpressure and the residue was purified by preparatory TLC(CH₂Cl₂:MeOH—NH₃ (7 N), 15:1) to afford 16.4 mg (65%) of 102. ¹H NMR(600 MHz, CDCl₃): δ 8.03 (s, 1H), 7.59 (d, J=8.5 Hz, 2H), 7.14-7.21 (m,3H), 7.04-7.09 (m, 4H), 5.93 (br s, 1H), 5.83 (t, J=5.8 Hz, 1H), 5.53(br s, 1H), 4.53 (d, J=5.8 Hz, 2H), 3.74-3.83 (m, 4H), 2.33-2.42 (m,4H), 2.28 (s, 3H); ¹³C NMR (150 MHz, CDCl₃): δ 168.5, 163.5, 162.0,161.8, 142.8, 138.8, 130.2, 128.6, 128.0, 127.30, 127.29, 125.3, 93.8,54.9, 46.2, 44.5, 43.7; MS (m/z): [M+H]⁺ 435.0.

Example 13

2-Chloro-4-((4-((4-methoxybenzyl)oxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)benzonitrile[105]

A mixture of 94 (0.920 g, 2.09 mmol) and K₂CO₃ (0.866 g, 6.27 mmol) inDMF (27 mL) was evacuated and backfilled with argon three times.Copper(I)thiophene-2-carboxylate (0.159 g, 0.832 mmol) was added andevacuated and backfilled with argon two times.2-Chloro-4-mercaptobenzonitrile (0.425 g, 2.51 mmol) was added and thereaction mixture was heated at 120° C. for 17 h. Solvent was removedunder reduced pressure and the residue was purified by columnchromatography (CH₂Cl₂:MeOH, 0-10% MeOH) to afford 0.504 g (50%) of 105.¹H NMR (600 MHz, CDCl₃): δ 8.21 (s, 1H), 7.39 (d, J=8.3 Hz, 1H),7.09-7.13 (m, 2H), 7.06 (d, J=1.7 Hz, 1H), 6.97 (dd, J=8.3, 1.8 Hz, 1H),6.79-6.83 (m, 2H), 5.30 (s, 2H), 3.91-3.96 (m, 4H), 3.80 (s, 3H),2.51-2.56 (m, 4H), 2.39 (s, 3H); ¹³C NMR (150 MHz, CDCl₃): δ 168.5,165.0, 161.8, 159.5, 147.6, 137.0, 133.4, 129.5, 128.0, 126.2, 124.1,116.2, 113.8, 108.9, 96.0, 67.8, 55.3, 54.7, 46.1, 43.8; HRMS (ESI) m/z[M+H]⁺ calcd. for C₂₄H₂₄ClN₅O₂S, 482.1417; found 482.1406.

2-Chloro-4-((4-hydroxy-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)benzonitrile[106]

To a solution of 105 (0.500 g, 1.04 mmol) in CH₂Cl₂ (4 mL) was added TFA(4 mL) dropwise over 5 minutes and stirred at rt for 12 h. The reactionmixture was concentrated under reduced pressure to give a residue whichwas purified by column chromatography (CH₂Cl₂:MeOH, 0-15% MeOH) toafford 0.354 g (94%) of 106. ¹H NMR (500 MHz, CDCl₃/MeOH-d₄): δ 8.14 (s,1H), 7.50 (d, J=8.3 Hz, 1H), 7.18 (d, J=1.7 Hz, 1H), 7.11 (dd, J=8.3,1.7 Hz, 1H), 3.85-4.28 (m, 4H), 3.09-3.27 (m, 4H), 2.82 (s, 3H); MS(ESI) m/z 362.2/364.3 [M+H]⁺.

2-Chloro-4-((4-chloro-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)benzonitrile[107]

106 (0.354 g, 0.978 mmol) and POCl₃ (2 mL) were heated at 75° C. for 1h. After cooling to rt, the reaction mixture was added to a beakercontaining ice chips. Following complete quenching of POCl₃, solidNa₂CO₃ was carefully added until pH˜9. This was transferred to aseperatory funnel and extracted with CH₂Cl₂ (3×100 mL), dried overMgSO₄, filtered and concentrated to a give 0.337 g (91%) of 107 whichwas used without further purification. ¹H NMR (500 MHz, CDCl₃): δ 8.38(s, 1H), 7.51 (d, J=8.3 Hz, 1H), 7.13 (d, J=1.8 Hz, 1H), 7.02 (dd,J=8.3, 1.8 Hz, 1H), 3.90-4.00 (m, 4H), 2.47-2.58 (m, 4H), 2.38 (s, 3H);MS (ESI) m/z 380.1/382.1 [M+H]⁺.

General Procedure for Synthesis of 108-118 and 121-126.

To alcohol (4.25 equiv.) dissolved in CH₃CN was added NaH (4 equiv.) andthe resulting suspension was stirred for 10 min. at rt. Then 107 (1equiv.) was added and the reaction mixture was stirred at rt for 3 h.Solvent was removed under reduced pressure and the residue was purifiedby column chromatography to afford intermediate nitrile. A mixture ofthe nitrile (1 equiv.) and KOH (25 equiv.) in t-BuOH was heated at 80°C. for 1 h. Solvent was removed under reduced pressure and the residuewas purified by preparatory TLC to afford desired amide.

2-Chloro-4-((4-((3-methoxybenzyl)oxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)benzamide[108]

108 was obtained in 26% yield following the general procedure above. ¹HNMR (600 MHz, CDCl₃): δ 8.25 (s, 1H), 7.65 (d, J=8.2 Hz, 1H), 7.20 (t,J=7.9 Hz, 1H), 7.08 (d, J=1.8 Hz, 1H), 7.00 (dd, J=8.3, 1.9 Hz, 1H),6.77-6.82 (m, 2H), 6.66 (s, 1H), 6.52 (br s, 1H), 5.98 (br s, 1H), 5.34(s, 2H), 3.87-3.93 (m, 4H), 3.72 (s, 3H), 2.47-2.52 (m, 4H), 2.36 (s,3H); ¹³C NMR (150 MHz, CDCl₃): δ 168.5, 167.5, 164.9, 161.7, 159.5,143.9, 137.8, 131.3, 131.1, 129.8, 129.4, 127.0, 124.5, 119.8, 113.23,113.20, 97.1, 67.7, 55.2, 54.7, 46.2, 43.8; HRMS (ESI) m/z [M+H]⁺ calcd.for C₂₄H₂₆ClN₅O₃S, 500.1523; found 500.1510.

2-Chloro-4-((4-((2-fluoro-5-methoxybenzyl)oxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)benzamide[109]

109 was obtained in 50% yield following the general procedure above. ¹HNMR (600 MHz, CDCl₃): δ 8.24 (s, 1H), 7.62 (d, J=8.2 Hz, 1H), 7.06 (d,J=1.8 Hz, 1H), 6.98 (dd, J=8.2, 1.8 Hz, 1H), 6.88-6.93 (m, 1H),6.69-6.74 (m, 1H), 6.54-6.58 (m, 1H), 6.47 (br s, 1H), 5.97 (br s, 1H),5.37 (s, 2H), 3.91-4.02 (m, 4H), 3.63 (s, 3H), 2.52-2.65 (m, 4H), 2.42(s, 3H); HRMS (ESI) m/z [M+H]⁺ calcd. for C₂₄H₂₅ClFN₅O₃S, 518.1429;found 518.1432.

2-Chloro-4-((4-((3-fluoro-5-methoxybenzyl)oxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)benzamide[110]

110 was obtained in 43% yield following the general procedure above. ¹HNMR (600 MHz, CD₂Cl₂/MeOH-d₄): δ 8.18 (s, 1H), 7.48 (d, J=8.2 Hz, 1H),7.02 (d, J=1.8 Hz, 1H), 6.97 (dd, J=8.2, 1.8 Hz, 1H), 6.42-6.46 (m, 2H),6.36-6.39 (m, 1H), 5.22 (s, 2H), 3.79-3.85 (m, 4H), 3.63 (s, 3H),2.40-2.47 (m, 4H), 2.28 (s, 3H); HRMS (ESI) m/z [M+H]⁺ calcd. forC₂₄H₂₅ClFN₅O₃S, 518.1429; found 518.1423.

2-Chloro-4-((4-((4-fluoro-3-methoxybenzyl)oxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)benzamide[111]

111 was obtained in 62% yield following the general procedure above. ¹HNMR (600 MHz, CDCl₃/MeOH-d₄): δ 8.28 (s, 1H), 7.55 (d, J=8.2 Hz, 1H),7.08 (s, 1H), 7.00-7.06 (m, 2H), 6.86-6.91 (m, 1H), 6.77-6.81 (m, 1H),5.35 (s, 2H), 3.89-3.97 (m, 4H), 3.76 (s, 3H), 2.51-2.57 (m, 4H), 2.38(s, 3H); ¹³C NMR (150 MHz, CDCl₃/MeOH-d₄): δ 168.9, 168.5, 165.5, 162.1,152.4 (d, J=244 Hz), 147.93, 147.86, 144.0, 133.2 (d, J=3.8 Hz), 131.8,131.0, 130.7, 127.1, 124.6, 120.4 (d, J=7.0 Hz), 116.1 (d, J=18.4 Hz),113.3 (d, J=2.0 Hz), 67.9, 56.4, 54.9, 46.0, 43.9; HRMS (ESI) m/z [M+H]⁺calcd. for C₂₄H₂₅ClFN₅O₃S, 518.1429; found 518.1418.

2-Chloro-4-((4-((2,4-difluoro-3-methoxybenzyl)oxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)benzamide[112]

112 was obtained in 62% yield following the general procedure above. ¹HNMR (600 MHz, CDCl₃): δ 8.19 (s, 1H), 7.58 (d, J=8.0 Hz, 1H), 6.93-6.99(m, 2H), 6.68-6.77 (m, 2H), 6.43 (br s, 1H), 5.97 (br s, 1H), 5.30 (s,2H), 3.85-3.97 (m, 7H), 2.47-2.58 (m, 4H), 2.36 (s, 3H); ¹³C NMR (150MHz, CDCl₃): δ 168.3, 167.4, 165.0, 161.5, 155.6 (dd, J=247.8, 4.9 Hz),153.8 (dd, J=248.4, 5.5 Hz), 143.6, 136.3 (t, J=14.1 Hz), 131.3, 131.1,130.1, 127.1, 124.7, 122.8, 120.4 (dd, J=12.9, 3.4 Hz), 112.0 (dd,J=19.4, 3.5 Hz), 97.5, 62.0, 61.2, 54.6, 45.8, 43.5; HRMS (ESI) m/z[M+H]⁺ calcd. for C₂₄H₂₄ClF₂N₅O₃S, 536.1335; found 536.1337.

2-Chloro-4-((4-((3-chloro-4-fluorobenzyl)oxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)benzamide[113]

113 was obtained in 48% yield following the general procedure above. ¹HNMR (500 MHz, CDCl₃): δ 8.25 (s, 1H), 7.69 (d, J=8.3 Hz, 1H), 7.20 (dd,J=7.0, 1.8 Hz, 1H), 6.97-7.07 (m, 4H), 6.41 (br s, 1H), 5.92 (br s, 1H),5.26 (s, 2H), 3.87-4.02 (m, 4H), 2.53-2.68 (m, 4H), 2.43 (s, 3H); ¹³CNMR (125 MHz, CDCl₃): δ 168.5, 167.3, 165.3, 161.7, 157.9 (d, J=248.1Hz), 143.8, 133.5 (d, J=3.9 Hz), 131.7, 130.2, 130.0, 127.5, 127.43,127.37, 124.9, 121.2 (d, J=17.9 Hz), 116.9 (d, J=21.2 Hz), 97.9, 66.8,54.7, 45.9, 43.6; HRMS (ESI) m/z [M+H]⁺ calcd. for C₂₃H₂₂Cl₂FN₅O₂S,522.0934; found 522.0920.

4-((4-((3-Bromo-4-fluorobenzyl)oxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)-2-chlorobenzamide[114]

114 was obtained in 47% yield following the general procedure above. ¹HNMR (500 MHz, CDCl₃): δ 8.25 (s, 1H), 7.70 (d, J=8.2 Hz, 1H), 7.37 (dd,J=6.5, 1.9 Hz, 1H), 6.98-7.08 (m, 4H), 6.41 (br s, 1H), 5.91 (br s, 1H),5.26 (s, 2H), 3.89-4.05 (m, 4H), 2.53-2.70 (m, 4H), 2.45 (s, 3H); ¹³CNMR (125 MHz, CDCl₃): δ 168.5, 167.3, 165.3, 161.7, 158.9 (d, J=246.6Hz), 143.8, 133.8 (d, J=3.8 Hz), 133.0, 131.69, 131.66, 130.2, 128.3 (d,J=7.4 Hz), 127.4, 124.9, 116.8 (d, J=22.3 Hz), 109.2 (d, J=21.2 Hz),98.0, 66.7, 54.6, 45.8, 43.5; HRMS (ESI) m/z [M+H]⁺ calcd. forC₂₃H₂₂BrClFN₅O₂S, 566.0428; found 566.0413.

2-Chloro-4-((4-((4-fluoro-3-(trifluoromethyl)benzyl)oxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)benzamide[115]

115 was obtained in 52% yield following the general procedure above. ¹HNMR (600 MHz, CDCl₃): δ 8.24 (s, 1H), 7.66 (d, J=8.2 Hz, 1H), 7.48 (dd,J=6.5, 1.6 Hz, 1H), 7.28-7.32 (m, 1H), 7.09-7.14 (m, 1H), 7.02 (d, J=1.8Hz, 1H), 6.99 (dd, J=8.3, 1.9 Hz, 1H), 6.40 (br s, 1H), 6.09 (br s, 1H),5.32 (s, 2H), 3.83-3.99 (m, 4H), 2.48-2.59 (m, 4H), 2.39 (s, 3H); ¹³CNMR (150 MHz, CDCl₃): δ 168.3, 167.3, 165.2, 161.5, 159.3 (d, J=255.5Hz), 143.7, 133.0 (d, J=8.6 Hz), 132.5 (d, J=3.8 Hz), 131.4, 131.3,130.0, 127.0, 126.4, 124.5, 122.4 (q, J=270.8 Hz), 118.2, 117.3 (d,J=20.8 Hz), 97.2, 66.5, 54.5, 45.9, 43.6; HRMS (ESI) m/z [M+H]⁺ calcd.for C₂₄H₂₂ClF₄N₅O₂S, 556.1197; found 556.1182.

2-Chloro-4-((4-((3-(dimethylamino)benzyl)oxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)benzamide[116]

116 was obtained in 67% yield following the general procedure above. ¹HNMR (600 MHz, CDCl₃): δ 8.22 (s, 1H), 7.61 (d, J=8.2 Hz, 1H), 7.10-7.14(m, 1H), 7.04 (d, J=1.8 Hz, 1H), 6.96 (dd, J=8.2, 1.8 Hz, 1H), 6.61 (dd,J=8.3, 2.4 Hz, 1H), 6.57 (s, 1H), 6.54 (d, J=7.5 Hz, 1H), 6.47 (br s,1H), 5.99 (br s, 1H), 5.31 (s, 2H), 3.88-3.97 (m, 4H), 2.82 (s, 6H),2.49-2.58 (m, 4H), 2.38 (s, 3H); ¹³C NMR (150 MHz, CDCl₃): δ 169.0,167.6, 165.2, 161.9, 150.8, 144.3, 137.2, 131.5, 131.4, 129.8, 129.3,127.0, 124.6, 115.9, 112.4, 111.8, 97.4, 68.7, 54.8, 46.1, 43.8, 40.7;HRMS (ESI) m/z [M+H]⁺ calcd. for C₂₅H₂₉ClN₆O₂S, 513.1839; found513.1833.

4-((4-((3-Aminobenzyl)oxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)-2-chlorobenzamide[117]

117 was obtained in 29% yield following the general procedure above. ¹HNMR (600 MHz, CD₂Cl₂/MeOH-d₄): δ 8.15 (s, 1H), 7.35 (d, J=8.2 Hz, 1H),7.03 (d, J=1.7 Hz, 1H), 6.93-6.99 (m, 4H), 6.50-6.56 (m, 2H), 6.28 (s,1H), 5.17 (s, 2H), 3.75-3.88 (m, 4H), 2.40-2.52 (m, 4H), 2.27 (s, 3H);¹³C NMR (150 MHz, CD₂Cl₂/MeOH-d₄): δ 168.8, 167.9, 163.8, 161.0, 146.3,142.3, 136.7, 130.8, 130.6, 129.0, 128.5, 126.4, 123.9, 117.0, 114.3,113.4, 97.1, 67.5, 53.8, 44.8, 42.7; HRMS (ESI) m/z [M+H]⁺ calcd. forC₂₃H₂₅ClN₆O₂S, 485.1526; found 485.1527.

4-((4-((3-Amino-4-fluorobenzyl)oxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)-2-chlorobenzamide[118]

118 was obtained in 53% yield following the general procedure above. ¹HNMR (500 MHz, CD₂Cl₂/MeOH-d₄): δ 8.15 (s, 1H), 7.34 (d, J=8.1 Hz, 1H),7.01 (d, J=1.5 Hz, 1H), 6.94 (dd, J=8.1, 1.5 Hz, 1H), 6.75-6.82 (m, 1H),6.43-6.49 (m, 1H), 6.35-6.41 (m, 1H), 5.13 (s, 2H), 3.75-3.84 (m, 4H),2.40-2.46 (m, 4H), 2.26 (s, 3H); HRMS (ESI) m/z [M+H]⁺ calcd. forC₂₃H₂₄ClFN₆O₂S, 503.1432; found 503.1430.

2-Chloro-4-((4-((3-(difluoromethoxy)benzyl)oxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)benzamide[121]

121 was obtained in 46% yield following the general procedure above. ¹HNMR (600 MHz, CDCl₃): δ 8.20 (s, 1H), 7.62 (d, J=8.2 Hz, 1H), 7.21 (t,J=7.9 Hz, 1H), 7.02 (d, J=1.8 Hz, 1H), 6.93-6.97 (m, 3H), 6.85-6.88 (m,1H), 6.39 (t, J=73.7 Hz, 1H), 6.36 (br s, 1H), 5.77 (br s, 1H), 5.28 (s,2H), 3.78-3.86 (m, 4H), 2.39-2.45 (m, 4H), 2.30 (s, 3H); HRMS (ESI) m/z[M+H]⁺ calcd. for C₂₄H₂₄ClF₂N₅O₃S, 536.1335; found 536.1324.

2-Chloro-4-((4-((3-hydroxybenzyl)oxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)benzamide[122]

122 was obtained in 52% yield as a byproduct from the synthesis of 121.¹H NMR (600 MHz, CDCl₃): δ 8.18 (s, 1H), 7.44 (s, 1H), 7.08-7.11 (m,1H), 7.04 (t, J=7.9 Hz, 1H), 6.94 (dd, J=8.2, 1.7 Hz, 1H), 6.66-6.70 (m,2H), 6.39 (br s, 1H), 6.07-6.13 (m, 1H), 5.99 (d, J=1.7 Hz, 1H), 5.11(s, 2H), 3.78-3.86 (m, 4H), 2.44-2.47 (m, 4H), 2.30 (s, 3H); ¹³C NMR(150 MHz, CDCl₃): δ 169.2, 167.9, 163.6, 161.6, 156.5, 143.5, 137.3,131.0, 130.5, 130.1, 129.3, 128.0, 125.7, 120.1, 116.1, 114.8, 98.4,68.2, 54.7, 46.1, 43.7; HRMS (ESI) m/z [M+H]⁺ calcd. for C₂₃H₂₄ClN₅O₃S,486.1367; found 486.1361.

2-Chloro-4-((4-((6-methoxypyridin-2-yl)methoxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)benzamide[123]

123 was obtained in 49% yield following the general procedure above. ¹HNMR (600 MHz, CDCl₃): δ 8.20 (s, 1H), 7.62 (d, J=8.2 Hz, 1H), 7.37-7.42(m, 1H), 7.04 (d, J=1.7 Hz, 1H), 7.00 (dd, J=8.2, 1.8 Hz, 1H), 6.57 (d,J=7.3 Hz, 1H), 6.53 (d, J=8.2 Hz, 1H), 6.38 (br s, 1H), 6.00 (br s, 1H),3.76-3.83 (m, 7H), 2.36-2.41 (m, 4H), 2.28 (s, 3H); ¹³C NMR (150 MHz,CDCl₃): δ 168.5, 167.4, 165.2, 163.5, 161.7, 154.1, 144.1, 139.1, 131.4,131.3, 129.8, 127.0, 124.6, 113.2, 109.4, 96.8, 68.3, 54.7, 53.4, 46.2,43.8; HRMS (ESI) m/z [M+H]⁺ calcd. for C₂₃H₂₅ClN₆O₃S, 501.1476; found501.1472.

2-Chloro-4-((4-((2-methoxypyridin-4-yl)methoxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)benzamide[124]

124 was obtained in 46% yield following the general procedure above. ¹HNMR (600 MHz, CDCl₃): δ 8.21 (s, 1H), 7.99 (d, J=5.3 Hz, 1H), 7.63 (d,J=8.2 Hz, 1H), 7.04 (d, J=1.8 Hz, 1H), 6.99 (dd, J=8.2, 1.9 Hz, 1H),6.60 (dd, J=5.3, 1.3 Hz, 1H), 6.44 (br s, 1H), 6.34 (s, 1H), 5.95 (br s,1H), 5.23 (s, 2H), 3.83 (s, 3H), 3.79 (m, 4H), 2.40 (m, 4H), 2.28 (s,3H); ¹³C NMR (150 MHz, CDCl₃): δ 168.1, 167.5, 165.1, 164.4, 161.6,148.2, 147.0, 143.6, 131.5, 131.2, 130.2, 127.2, 124.7, 114.8, 108.4,97.2, 66.0, 54.7, 53.5, 46.2, 43.9; HRMS (ESI) m/z [M+H]⁺ calcd. forC₂₃H₂₅ClN₆O₃S, 501.1476; found 501.1462.

2-Chloro-4-((4-((5-methoxypyridin-3-yl)methoxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)benzamide[125]

125 was obtained in 49% yield following the general procedure above. ¹HNMR (600 MHz, CDCl₃): δ 8.22 (s, 1H), 8.08 (br s, 1H), 7.49 (br s, 2H),7.42 (d, J=8.1 Hz, 1H), 7.00 (d, J=1.7 Hz, 1H), 6.95 (dd, J=8.1, 1.8 Hz,1H), 6.91-6.93 (m, 1H), 5.94 (br s, 1H), 5.25 (s, 2H), 3.87-3.94 (m,4H), 3.72 (s, 3H), 2.51-2.59 (m, 4H), 2.38 (s, 3H); ¹³C NMR (150 MHz,CDCl₃): δ 168.3, 167.8, 164.3, 161.4, 155.4, 142.4, 141.1, 136.5, 132.4,131.8, 131.4, 130.2, 127.8, 125.4, 120.4, 98.9, 65.1, 55.6, 54.5, 45.8,43.4; HRMS (ESI) m/z [M+H]⁺ calcd. for C₂₃H₂₅ClN₆O₃S, 501.1476; found501.1467.

2-Chloro-4-((4-((4-methoxypyridin-2-yl)methoxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)benzamide[126]

126 was obtained in 39% yield following the general procedure above. ¹HNMR (600 MHz, CDCl₃): δ 8.25 (d, J=5.7 Hz, 1H), 8.22 (s, 1H), 7.63 (d,J=8.3 Hz, 1H), 7.09 (d, J=1.8 Hz, 1H), 7.01 (dd, J=8.3, 1.8 Hz, 1H),6.61 (dd, J=5.8, 2.5 Hz, 1H), 6.52 (d, J=2.3 Hz, 1H), 6.40 (br s, 1H),5.98 (br s, 1H), 5.36 (s, 2H), 3.81-3.92 (m, 4H), 3.65 (s, 3H),2.45-2.55 (m, 4H), 2.35 (s, 3H); ¹³C NMR (150 MHz, CDCl₃): δ 167.3,166.2, 165.4, 164.2, 160.6, 157.1, 149.3, 142.9, 130.5, 130.4, 128.9,125.9, 123.4, 107.5, 105.6, 96.0, 67.3, 54.0, 53.5, 44.7, 42.3; HRMS(ESI) m/z [M+H]⁺ calcd. for C₂₃H₂₅ClN₆O₃S, 501.1476; found 501.1487.

Example 14

2-Chloro-4-((4-((4-fluoro-3-hydroxybenzyl)oxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)benzamide[127]

A mixture of 111 (19 mg, 0.0367 mmol) and boron trichloride methylsulfide complex (26 mg, 0.147 mmol) in 1,2-dichloroethane (1 mL) washeated at 80° C. overnight. Solvents were removed under reduced pressureand the resulting residue was purified by column chromatography(CH₂Cl₂:MeOH, 0-10% MeOH) to give 2.8 mg (15%) of 127. ¹H NMR (600 MHz,CDCl₃): δ 8.25 (s, 1H), 7.55 (d, J=8.2 Hz, 1H), 7.12 (d, J=1.7 Hz, 1H),7.01 (dd, J=8.2, 1.8 Hz, 1H), 6.91-6.96 (m, 1H), 6.66-6.70 (m, 1H), 6.41(br s, 1H), 6.31 (d, J=8.3 Hz, 1H), 5.99 (br s, 1H), 5.17 (s, 2H),3.86-3.93 (m, 4H), 2.48-2.52 (m, 4H), 2.36 (s, 3H); HRMS (ESI) m/z[M+H]⁺ calcd. for C₂₃H₂₃ClFN₅O₃S, 504.1272; found 504.1263.

Example 15

4-((4-((4-Methoxybenzyl)oxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)-2-(trifluoromethyl)benzonitrile[128]

A mixture of 94 (1.5 g, 3.4 mmol) and K₂CO₃ (1.41 g, 10.2 mmol) in DMF(44 mL) was evacuated and backfilled with argon three times.Copper(I)thiophene-2-carboxylate (0.259 g, 1.36 mmol) was added andevacuated and backfilled with argon two times.4-Mercapto-2-(trifluoromethyl)benzonitrile (0.829 g, 4.08 mmol) wasadded and the reaction mixture was heated at 120° C. for 23 h. Solventwas removed under reduced pressure and the residue was purified bycolumn chromatography (CH₂Cl₂:MeOH, 0-10% MeOH) to afford 1.66 g (95%)of 128. ¹H NMR (600 MHz, CDCl₃): δ 8.29 (s, 1H), 7.57 (d, J=8.2 Hz, 1H),7.44 (s, 1H), 7.19 (d, J=8.2 Hz, 1H), 7.08 (d, J=8.5 Hz, 2H), 6.82 (d,J=8.6 Hz, 2H), 5.31 (s, 2H), 3.70-3.88 (m, 7H), 2.73 (m, 4H), 1.60 (s,3H); MS (ESI) m/z 516.2 [M+H]⁺.

4-((4-Hydroxy-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)-2-(trifluoromethyl)benzonitrile[129]

To a solution of 128 (1.66 g, 3.2 mmol) in CH₂Cl₂ (15 mL) was added TFA(15 mL) dropwise over 5 minutes and stirred at rt for 5 h. The reactionmixture was concentrated under reduced pressure to give a residue whichwas purified by column chromatography (CH₂Cl₂:MeOH, 0-20% MeOH) toafford 1.21 g (95%) of 129. ¹H NMR (500 MHz, CDCl₃/MeOH-d₄): δ 8.11 (s,1H), 7.64 (d, J=8.2 Hz, 1H), 7.48 (d, J=2.7 Hz, 1H), 7.34 (dd, J=8.2,1.6 Hz, 1H), 3.91 (m, 4H), 2.73 (m, 4H), 2.54 (s, 1H); MS (ESI) m/z396.1 [M+H]⁺.

4-((4-Chloro-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)-2-(trifluoromethyl)benzonitrile[130]

129 (0.826 g, 2.09 mmol) and POCl₃ (5 mL) were heated at 75° C. for 1 h.After cooling to rt, the reaction mixture was added to a beakercontaining ice chips. Following complete quenching of POCl₃, solidNa₂CO₃ was carefully added until pH˜9. This was transferred to aseperatory funnel and extracted with CH₂Cl₂ (3×100 mL), dried overMgSO₄, filtered and concentrated to a give 0.707 g (82%) of 130 whichwas used without further purification. ¹H NMR (500 MHz, CDCl₃): δ 8.36(s, 1H), 7.61 (d, J=8.2 Hz, 1H), 7.39 (s, 1H), 7.17 (d, J=8.2 Hz, 1H),3.90 (m, 4H), 2.59 (m, 4H), 1.48 (s, 3H); MS (ESI) m/z 414.1 [M+H]⁺.

General Procedure for Synthesis of 131-139.

To alcohol (4.25 equiv.) dissolved in CH₃CN was added NaH (4 equiv.) andthe resulting suspension was stirred for 10 min. at rt. Then 130 (1equiv.) was added and the reaction mixture was stirred at rt for 3 h.Solvent was removed under reduced pressure and the residue was purifiedby column chromatography to afford intermediate nitrile. A mixture ofthe nitrile (1 equiv.) and KOH (25 equiv.) in t-BuOH was heated at 80°C. for 1 h. Solvent was removed under reduced pressure and the residuewas purified by preparatory TLC to afford the desired amide.

4-((4-((3-Chlorobenzyl)oxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)-2-(trifluoromethyl)benzamide[131]

131 was obtained in 47% yield following the general procedure above. ¹HNMR (600 MHz, CDCl₃): δ 8.21 (s, 1H), 7.36-7.39 (m, 2H), 7.13-7.17 (m,3H), 7.07 (s, 1H), 6.95-6.98 (m, 1H), 5.87 (br s, 1H), 5.73 (br s, 1H),5.24 (s, 2H), 3.82-3.97 (m, 4H), 2.47-2.60 (m, 4H), 2.37 (s, 3H); ¹³CNMR (150 MHz, CDCl₃): δ 169.1, 168.4, 165.0, 161.5, 141.9, 138.2, 134.2,131.6, 129.9, 129.21, 129.18, 128.1, 127.8 (d, J=31.9 Hz), 127.5, 125.4,123.9 (q, J=5.2 Hz), 123.2 (q, J=272.4 Hz), 97.5, 67.1, 54.5, 45.7,43.4; HRMS (ESI) m/z [M+H]⁺ calcd. for C₂₄H₂₃ClF₃N₅O₂S, 538.1291; found538.1287.

4-((4-((3-Chloro-4-fluorobenzyl)oxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)-2-(trifluoromethyl)benzamide[132]

132 was obtained in 48% yield following the general procedure above. ¹HNMR (600 MHz, CDCl₃): δ 8.21 (s, 1H), 7.34-7.39 (m, 2H), 7.13-7.17 (m,2H), 6.98-7.02 (m, 1H), 6.93-6.97 (m, 1H), 5.91 (br s, 1H), 5.73 (br s,1H), 5.21 (s, 2H), 3.83-3.98 (m, 4H), 2.48-2.64 (m, 4H), 2.37 (s, 3H);¹³C NMR (150 MHz, CDCl₃): δ 169.1, 168.3, 165.1, 161.5, 158.5, 156.9,141.9, 133.2 (d, J=3.9 Hz), 131.6, 129.8, 129.2, 127.6 (q, J=32.0 Hz),127.3 (d, J=7.2 Hz), 123.9 (q, J=5.2 Hz), 123.2 (q, J=272.3 Hz), 120.9(d, J=17.8 Hz), 116.7 (d, J=21.0 Hz), 97.4, 66.6, 54.5, 45.8, 43.4; HRMS(ESI) m/z [M+H]⁺ calcd. for C₂₄H₂₂ClF₄N₅O₂S, 556.1197; found 556.1200.

4-((4-((5-Chloro-2-fluorobenzyl)oxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)-2-(trifluoromethyl)benzamide[133]

133 was obtained in 53% yield following the general procedure above. ¹HNMR (500 MHz, CDCl₃): δ 8.22 (s, 1H), 7.36-7.42 (m, 2H), 7.12-7.18 (m,2H), 7.01-7.05 (m, 1H), 6.87-6.93 (m, 1H), 5.90 (br s, 1H), 5.73 (br s,1H), 5.30 (s, 2H), 3.88-4.06 (m, 4H), 2.55-2.72 (m, 4H), 2.43 (s, 3H);HRMS (ESI) m/z [M+H]⁺ calcd. for C₂₄H₂₂ClF₄N₅O₂S, 556.1197; found556.1199.

4-((4-((3-Bromo-4-fluorobenzyl)oxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)-2-(trifluoromethyl)benzamide[134]

134 was obtained in 51% yield following the general procedure above. ¹HNMR (600 MHz, CDCl₃): δ 8.21 (s, 1H), 7.38 (d, J=8.1 Hz, 1H), 7.35 (d,J=1.4 Hz, 1H), 7.33 (dd, J=6.7, 1.7 Hz, 1H), 7.14 (dd, J=8.1, 1.6 Hz,1H), 6.96-7.01 (m, 2H), 5.89 (br s, 1H), 5.73 (br s, 1H), 5.21 (s, 2H),3.83-4.02 (m, 4H), 2.49-2.67 (m, 4H), 2.40 (s, 3H); ¹³C NMR (150 MHz,CDCl₃): δ 169.1, 168.3, 165.1, 161.5, 159.5, 157.9, 141.8, 133.6 (d,J=3.8 Hz), 132.7, 131.6, 129.2 (d, J=5.1 Hz), 128.1 (d, J=7.3 Hz), 127.8(q, J=32.0 Hz), 123.9 (q, J=5.2 Hz), 123.2 (q, J=272.3 Hz), 116.6 (d,J=22.4 Hz), 108.9 (d, J=21.3 Hz), 97.5, 66.6, 54.4, 45.7, 43.3; HRMS(ESI) m/z [M+H]⁺ calcd. for C₂₄H₂₂BrF₄N₅O₂S, 600.0692; found 600.0697.

4-((4-((2,4-Difluorobenzyl)oxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)-2-(trifluoromethyl)benzamide[135]

135 was obtained in 57% yield following the general procedure above. ¹HNMR (600 MHz, CDCl₃): δ 8.20 (s, 1H), 7.33-7.37 (m, 2H), 7.14-7.18 (m,1H), 6.98-7.04 (m, 1H), 6.67-6.75 (m, 2H), 5.87 (br s, 1H), 5.71 (br s,1H), 5.29 (s, 2H), 3.80-4.05 (m, 4H), 2.46-2.68 (m, 4H), 2.38 (3, 3H);¹³C NMR (150 MHz, CDCl₃): δ 169.1, 168.3, 165.0, 162.8 (dd, J=248.3,11.9 Hz), 161.5, 160.6 (dd, J=248.9, 12.0 Hz), 141.9, 131.6, 130.7 (dd,J=9.7, 5.4 Hz), 129.5, 129.1, 127.7 (q, J=31.9 Hz), 124.2 (q, J=5.1 Hz),123.2 (q, J=272.3 Hz), 119.3 (dd, J=14.5, 3.8 Hz), 111.5 (dd, J=21.1,3.5 Hz), 103.8 (t, J=25.4 Hz), 97.7, 61.2, 54.5, 45.7, 43.3; HRMS (ESI)m/z [M+H]⁺ calcd. for C₂₄H₂₂F₅N₅O₂S, 540.1493; found 540.1476.

4-((4-((3-Methoxybenzyl)oxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)-2-(trifluoromethyl)benzamide[136]

136 was obtained in 52% yield following the general procedure above. ¹HNMR (600 MHz, CDCl₃): δ 8.20 (s, 1H), 7.38 (d, J=1.4 Hz, 1H), 7.30 (d,J=8.1 Hz, 1H), 7.11-7.15 (m, 1H), 7.09 (dd, J=8.1, 1.5 Hz, 1H),6.68-6.74 (m, 2H), 6.49 (s, 1H), 5.92 (br s, 1H), 5.87 (br s, 1H), 5.24(s, 2H), 3.82-3.97 (m, 4H), 3.64 (s, 3H), 2.46-2.58 (m, 4H), 2.36 (s,3H); ¹³C NMR (150 MHz, CDCl₃): δ 169.3, 168.4, 164.8, 161.6, 159.4,142.5, 137.7, 131.5, 129.5, 129.1, 129.0, 127.7 (q, J=32.0 Hz), 124.0(q, J=5.2 Hz), 123.2 (q, J=272.4 Hz), 119.9, 113.5, 113.1, 97.6, 67.8,55.2, 54.5, 45.8, 43.5; HRMS (ESI) m/z [M+H]⁺ calcd. for C₂₅H₂₆F₃N₅O₃S,534.1787; found 534.1787.

4-((4-((4-Fluoro-3-methoxybenzyl)oxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)-2-(trifluoromethyl)benzamide[137]

137 was obtained in 63% yield following the general procedure above. ¹HNMR (600 MHz, CDCl₃) δ 2.40 (s, 3H), 2.54 (m, 4H), 3.72 (s, 3H), 3.94(m, 4H), 5.31 (s, 2H), 5.95 (bs, 2H), 6.74-6.77 (m, 2H), 6.97-7.00 (m,1H), 7.10 (dd, J=8.1, 1.7 Hz, 1H), 7.34 (d, J=8.2 Hz, 1H), 7.41 (d,J=1.7 Hz, 1H), 8.27 (s, 1H); ¹³C NMR (150 MHz, CDCl₃) δ 43.9, 46.2,54.9, 56.5, 67.6, 97.2, 113.4, 116.1, 120.6, 123.9, 127.9, 128.9, 129.2,131.7, 132.7, 142.3, 147.6, 151.5, 53.1, 161.9, 165.3, 168.7, 169.3;HRMS (ESI) m/z [M+H]⁺ calcd. for C₂₅H₂₆F₄N₅O₃S 552.1692; found 552.1687.

4-((4-((2-Fluoro-5-methoxybenzyl)oxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)-2-(trifluoromethyl)benzamide[138]

138 was obtained in 60% yield following the general procedure above. ¹HNMR (600 MHz, CDCl₃): δ 8.21 (s, 1H), 7.39 (d, J=1.6 Hz, 1H), 7.32 (d,J=8.1 Hz, 1H), 7.10 (dd, J=8.1, 1.7 Hz, 1H), 6.86 (m, 1H), 6.65-6.69 (m,1H), 6.41-6.44 (m, 1H), 5.93 (br s, 1H), 5.88 (br s, 1H), 5.30 (s, 2H),3.90 (m, 4H), 3.59 (s, 3H), 2.53 (s, 4H), 2.37 (s, 3H); HRMS (ESI) m/z[M+H]⁺ calcd. for C₂₅H₂₅F₄N₅O₃S, 552.1692; found 552.1699.

4-((4-((3-(Dimethylamino)benzyl)oxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)-2-(trifluoromethyl)benzamide[139]

139 was obtained in 68% yield following the general procedure above. ¹HNMR (600 MHz, CDCl₃): δ 8.18 (s, 1H), 7.37 (d, J=1.5 Hz, 1H), 7.24 (d,J=8.1 Hz, 1H), 7.05-7.09 (m, 1H), 7.03 (dd, J=8.1, 1.6 Hz, 1H),6.56-6.59 (m, 1H), 6.47-6.52 (m, 2H), 5.88 (br s, 1H), 5.84 (br s, 1H),5.26 (s, 2H), 3.83-3.96 (m, 4H), 2.76 (s, 6H), 2.45-2.55 (m, 4H), 2.35(s, 3H); HRMS (ESI) m/z [M+H]⁺ calcd. for C₂₆H₂₉F₃N₆O₂S, 547.2103; found547.2090.

Example 16

4-((4-((3-Chlorobenzyl)amino)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)-2-(trifluoromethyl)benzamide[140]

A solution of 130 (15 mg, 0.036245 mmol), 3-chlorobenzylamine (22.1 μL,0.181 mmol) in CH₃CN (500 μL) was heated at 75° C. for 3 h. The reactionmixture was concentrated under reduced pressure to give a residue whichwas purified by preparatory TLC (CH₂Cl₂:MeOH—NH₃ (7 N), 10:1) to afford6 mg (32%) of 140. ¹H NMR (500 MHz, CDCl₃/MeOH-d₄): δ 8.00 (s, 1H), 7.58(d, J=8.3 Hz, 1H), 7.42 (d, J=1.3 Hz, 1H), 7.11-7.19 (m, 3H), 7.07 (s,1H), 6.95-7.00 (m, 1H), 5.90 (t, J=5.9 Hz, 1H), 4.50 (d, J=5.9 Hz, 2H),3.75-3.89 (m, 4H), 2.40-2.45 (m, 4H), 2.29 (s, 3H); MS (ESI) m/z 519.1[M+H]⁺.

4-((4-((3-Chlorobenzyl)amino)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)-2-(trifluoromethyl)benzamide[141]

A mixture of 140 (6 mg, 0.0116 mmol) and KOH (49 mg, 0. mmol) in t-BuOH(400 μL) was heated at 80° C. for 1 h. Solvent was removed under reducedpressure and the residue was purified by preparatory TLC(CH₂Cl₂:MeOH—NH₃ (7 N), 10:1) to afford 4.6 mg (74%) of 141. ¹H NMR (600MHz, CDCl₃): δ 8.05 (s, 1H), 7.43 (d, J=8.1 Hz, 1H), 7.36 (d, J=1.3 Hz,1H), 7.11-7.16 (m, 3H), 7.07 (s, 1H), 6.95-6.99 (m, 1H), 5.90-5.95 (t,J=5.5 Hz, 1H), 5.78 (br s, 1H), 5.72 (br s, 1H), 4.49 (d, J=5.9 Hz, 2H),3.99 (m, 4H), 2.72 (m, 4H), 2.52 (s, 3H); HRMS (ESI) m/z [M+H]⁺ calcd.for C₂₄H₂₄ClF₃N₆OS, 537.1451; found 537.1459.

Example 17

5-((4-Methoxybenzyl)thio)pyridin-2-amine [143]

A mixture of 142 (0.220 g, 1.0 mmol), K₂CO₃ (0.552 g, 4.0 mmol), CuI(0.078 g, 0.4 mmol) and neocuproine (0.090 g, 0.4 mmol) in DMF (5 mL)was evacuated and backfilled with argon three times.(4-methoxyphenyl)methanethiol (0.185 g, 1.2 mmol) was added and thereaction mixture was heated at 135° C. for 18 h. Solvent was removedunder reduced pressure and the residue was purified by columnchromatography (CH₂Cl₂:MeOH, 0-10% MeOH) to afford 185 mg (75%) of 143.MS (m/z): [M+H]⁺ 247.1.

Bis((6-aminopyridin-3-yl)thio)mercury [144]

To a solution of 143 (1.0 g, 4.1 mmol) in TFA (10 mL) was added HgO(0.45 g, 2.05 mmol) and the mixture was heated to 60° C. for 1 h. Thereaction mixture was concentrated under reduced pressure and theresulting residue was purified by column chromatography (CH₂Cl₂:MeOH,9:1) to afford 0.85 g (92%) of 144.

General Procedure for the Synthesis of 146c/e/g/h.

A mixture of 145c/e/g/h (1 equiv.), 144 (1.2 equiv.), K₂CO₃ (4 equiv.),CuI (1.0 equiv.) and neocuproine (0.2 equiv.) in DMF was heated at 140°C. for 1 h under argon. The reaction mixture was concentrated underreduced pressure and purified by preparatory TLC.

5-((4-((4-Fluorobenzyl)oxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)pyridin-2-amine[146c]

146c was obtained in 63% yield following the general procedure above. ¹HNMR (500 MHz, CDCl₃): δ 8.13 (s, 1H), 8.03 (s, 1H), 7.30 (dd, J=8.5, 1.8Hz, 1H), 7.15-7.19 (m, 2H), 6.92-6.95 (m, 2H), 6.26 (d, J=8.5 Hz, 1H),5.24 (s, 2H), 4.38 (s, 2H), 3.74-3.76 (m, 4H), 2.27-2.39 (m, 4H), 2.27(s, 3H); MS (m/z): [M+H]⁺ 427.0.

5-((2-(4-Methylpiperazin-1-yl)-4-((3-(trifluoromethyl)benzyl)oxy)pyrimidin-5-yl)thio)pyridin-2-amine[146e]

146e was obtained in 52% yield following the general procedure above. ¹HNMR (600 MHz, CDCl₃): δ 8.17 (s, 1H), 8.07 (s, 1H), 7.57 (d, J=7.6 Hz,1H), 7.40 (t, J=7.5 Hz, 1H), 7.37 (dd, J=8.6, 2.3 Hz, 1H), 7.28-7.32 (m,2H), 6.31 (d, J=8.5 Hz, 1H), 5.32 (s, 2H), 4.39 (s, 2H), 3.67-3.70 (m,4H), 2.28-2.33 (m, 4H), 2.24 (s, 3H); ¹³C NMR (150 MHz, CDCl₃): δ 167.5,162.8, 160.9, 157.5, 151.1, 141.5, 135.4, 132.1, 128.0, 127.5, 126.9,125.7, 120.7, 108.8, 63.6, 54.7, 46.2, 43.8; MS (m/z): [M+H]⁺ 477.0.

5-((4-((3,4-Difluorobenzyl)oxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)pyridin-2-amine[146g]. 146g was obtained in 68% yield following the general procedureabove. MS (m/z): [M+H]⁺ 444.9.

5-((4-((3,5-Bis(trifluoromethyl)benzyl)oxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)pyridin-2-amine[146h]. 146h was obtained in 47% yield following the general procedureabove. MS (m/z): [M+H]⁺ 545.0.

Example 18

4-((4-Methoxybenzyl)oxy)-2-(4-methylpiperazin-1-yl)-5-((6-nitropyridin-3-yl)thio)pyrimidine[147]

A mixture of 94 (0.760 g, 1.726 mmol) and K₂CO₃ (0.714 g, 5.178 mmol) inDMF (20 mL) was evacuated and backfilled with argon three times.Copper(I)thiophene-2-carboxylate (0.132 g, 0.690 mmol) was added andevacuated and backfilled with argon two times. 6-Nitropyridine-3-thiol(0.350 g, 2.24 mmol) was added and the reaction mixture was heated at130° C. for 3 h. Solvent was removed under reduced pressure and theresidue was purified by column chromatography (CH₂Cl₂:MeOH, 0-10% MeOH)to afford 0.600 g (74%) of 147. MS (m/z): [M+H]⁺ 469.0.

2-(4-Methylpiperazin-1-yl)-5-((6-nitropyridin-3-yl)thio)pyrimidin-4-ol[148]

To a solution of 147 (0.600 g, 1.28 mmol) in CH₂Cl₂ (10 mL) was addedTFA (1 mL) dropwise over 5 minutes and stirred at rt for overnight. Thereaction mixture was concentrated under reduced pressure to give aresidue which was purified by column chromatography (CH₂Cl₂:MeOH, 0-20%MeOH) to afford 0.280 g (63%) of 148. ¹H NMR (500 MHz, DMSO-d₆): δ 8.37(d, J=2.4 Hz, 1H), 8.22 (s, 1H), 8.19 (d, J=8.7 Hz, 1H), 7.80 (dd,J=8.6, 2.5 Hz, 1H), 3.25-3.28 (m, 4H), 2.78 (s, 3H), 2.49-2.51 (m, 4H);MS (m/z): [M+H]⁺ 349.1.

4-Chloro-2-(4-methylpiperazin-1-yl)-5-((6-nitropyridin-3-yl)thio)pyrimidine[149]

148 (0.240 g, 0.69 mmol) and POCl₃ (5 mL) were heated at 80° C. for 1 h.After cooling to rt, the reaction mixture was added to a beakercontaining ice chips. Following complete quenching of POCl₃, solidNa₂CO₃ was carefully added until pH˜9. This was transferred to aseparatory funnel and extracted with CH₂Cl₂ (3×75 mL), dried over MgSO₄,filtered and concentrated to a give 0.180 g (71%) of 149 which was usedwithout further purification. MS (ESI) m/z [M+H]⁺ 367.1.

5-((4-Chloro-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)pyridin-2-amine[150]

A mixture of 149 (140 mg, 0.382 mmol), iron (10 mg, 0.179 mmol) in AcOH(1 mL) was stirred at rt for 2 h. The reaction mixture was concentratedunder reduced pressure to give a residue which was purified by columnchromatography (CH₂Cl₂:MeOH, 0-10% MeOH) to afford 70 mg (54%) of 150.MS (ESI) m/z [M+H]⁺ 337.1.

General Procedure for Synthesis of 151-158.

To alcohol (4.25 equiv.) dissolved in CH₃CN was added NaH (4 equiv.) andthe resulting suspension was stirred for 10 min. at rt. Then 150 (1equiv.) was added and the reaction mixture was stirred at rt for 3 h.Solvent was removed under reduced pressure and the residue was purifiedby preparatory TLC to afford the desired product.

5-((4-((4-Fluoro-3-methoxybenzyl)oxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)pyridin-2-amine[151]

151 was obtained in 81% yield following the general procedure above. ¹HNMR (500 MHz, CDCl₃) δ 8.22 (s, 1H), 8.11 (s, 1H), 7.38-7.40 (m, 1H),7.01-7.05 (m, 1H), 6.93-6.95 (m, 1H), 6.82-6.84 (m, 1H), 6.32 (d, J=8.5Hz, 1H), 5.31 (s, 2H), 4.49 (br s, 2H), 3.85 (m, 7H), 2.49-2.52 (m, 4H),2.38 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 168.0, 162.7, 161.2, 157.7,151.3, 147.8, 141.7, 133.0, 120.7, 120.3, 116.1, 115.9, 113.1, 108.9,103.4, 67.6, 56.4, 54.9, 46.2, 43.8; HRMS (ESI) m/z [M+H]⁺ calcd. forC₂₂H₂₆FN₆O₂S 457.1822; found 457.1809.

3-(((5-((6-Aminopyridin-3-yl)thio)-2-(4-methylpiperazin-1-yl)pyrimidin-4-yl)oxy)methyl)benzonitrile[152]

152 was obtained in 70% yield following the general procedure above. ¹HNMR (500 MHz, CDCl₃) δ 8.26 (s, 1H), 8.10 (d, J=2.2 Hz, 1H), 7.58 (d,J=7.6 Hz, 1H), 7.50 (m, 1H), 7.41-7.46 (m, 2H), 7.39 (s, 1H), 6.45 (d,J=8.5 Hz, 1H), 5.37 (s, 2H), 4.56 (br s, 2H), 3.85 (m, 4H), 2.51 (m,4H), 2.39 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 167.6, 162.8, 161.0,157.9, 151.3, 141.5, 138.4, 131.9, 131.7, 131.1, 129.4, 120.4, 118.8,112.8, 109.2, 103.2, 66.6, 54.8, 46.1, 43.7; HRMS (ESI) m/z [M+H]⁺calcd. for C₂₂H₂₄N₇O₂S 434.1763; found 434.1751.

5-((4-((3-(Dimethylamino)benzyl)oxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)pyridin-2-amine[153]

153 was obtained in 75% yield following the general procedure above. ¹HNMR (500 MHz, CDCl₃) δ 8.19 (s, 1H), 8.14 (d, J=2.0 Hz, 1H), 7.42 (dd,J=8.5, 2.4 Hz, 1H), 7.20 (t, J=7.9 Hz, 1H), 6.74 (s, 1H), 6.66-6.68 (m,2H), 6.33 (d, J=8.5 Hz, 1H), 5.34 (s, 2H), 4.46 (br s, 2H), 3.86 (m,4H), 2.94 (s, 6H), 2.47-2.49 (m, 4H), 2.37 (s, 3H); ¹³C NMR (125 MHz,CDCl₃) δ 168.2, 162.6, 161.2, 157.7, 151.4, 150.9, 141.9, 137.5, 129.3,120.9, 116.1, 112.2, 111.9, 108.9, 103.4, 68.7, 54.9, 46.2, 43.8, 40.8;HRMS (ESI) m/z [M+H]⁺ calcd. for C₂₃H₃₀N₇OS 452.2233; found 452.2215.

5-((4-((3-Chloro-4-fluorobenzyl)oxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)pyridin-2-amine[154]

154 was obtained in 80% yield following the general procedure above. ¹HNMR (500 MHz, CDCl₃) δ 8.22 (s, 1H), 8.10 (d, J=2.1 Hz, 1H), 7.39 (dd,J=8.5, 2.4 Hz, 1H), 7.30 (dd, J=7.0, 1.9 Hz, 1H), 7.07-7.14 (m, 2H),6.36 (d, J=8.5 Hz, 1H), 5.29 (s, 2H), 4.48 (br s, 2H), 3.80-3.82 (m,4H), 2.43-2.45 (m, 4H), 2.33 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 167.7,162.8, 161.1, 157.8, 156.9, 151.3, 141.6, 133.9, 130.2, 127.7, 120.7,116.8, 116.7, 108.9, 103.2, 66.5, 55.0, 46.4, 44.1; HRMS (ESI) m/z[M+H]⁺ calcd. for C₂₁H₂₃ClFN₆OS 461.1327; found 461.1316.

5-((4-((3-Bromo-4-fluorobenzyl)oxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)pyridin-2-amine[155]

155 was obtained in 73% yield following the general procedure above. ¹HNMR (500 MHz, CDCl₃) δ 8.22 (s, 1H), 8.11 (s, 1H), 7.48 (dd, J=6.5, 1.9Hz, 1H), 7.40 (dd, J=8.5, 2.3 Hz, 1H), 7.17-7.20 (m, 1H), 7.07 (t, J=8.4Hz, 1H), 6.39 (d, J=8.5 Hz, 1H), 5.29 (s, 2H), 4.50 (br s, 2H), 3.86 (m,4H), 2.51 (m, 4H), 2.38 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 167.7,162.7, 161.0, 157.9, 157.8, 151.4, 141.7, 134.2, 133.1, 128.6, 128.5,116.7, 116.6, 109.2, 109.1, 66.5, 54.8, 46.1, 43.8; HRMS (ESI) m/z[M+H]⁺ calcd. for C₂₁H₂₃BrFN₆OS 505.0821; found 505.0821.

5-((4-((4-Fluoro-3-(trifluoromethyl)benzyl)oxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)pyridin-2-amine[156]

156 was obtained in 68% yield following the general procedure above. ¹HNMR (500 MHz, CDCl₃) δ 8.21 (s, 1H), 8.08 (d, J=2.0 Hz, 1H), 7.55 (d,J=6.6 Hz, 1H), 7.40-7.43 (m, 1H), 7.37 (dd, J=8.5, 2.3 Hz, 1H), 7.16 (t,J=9.3 Hz, 1H), 6.34 (d, J=8.5 Hz, 1H), 5.34 (s, 2H), 4.49 (br s, 2H),3.84 (m, 4H), 2.48-2.50 (m, 4H), 2.37 (s, 3H); HRMS (ESI) m/z [M+H]⁺calcd. for C₂₂H₂₃F₄N₆OS 495.1590; found 495.1577.

5-((4-((2-Fluoro-5-methoxybenzyl)oxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)pyridin-2-amine[157]

157 was obtained in 96% yield following the general procedure above. ¹HNMR (500 MHz, CDCl₃) δ 8.19 (s, 1H), 8.12 (s, 1H), 7.42 (dd, J=8.5, 2.2Hz, 1H), 6.96 (t, J=9.2 Hz, 1H), 6.84-6.86 (m, 1H), 6.76-6.79 (m, 1H),6.34 (d, J=8.5 Hz, 1H), 5.40 (s, 2H), 4.48 (br s, 2H), 3.83 (m, 4H),3.73 (s, 3H), 2.45-2.47 (m, 4H), 2.34 (s, 3H); ¹³C NMR (125 MHz, CDCl₃)δ 167.9, 162.8, 161.1, 157.8, 155.9, 151.4, 141.8, 124.6, 120.7, 116.0,115.9, 114.9, 114.3, 109.0, 103.3, 61.7, 56.0, 54.9, 46.2, 43.9; HRMS(ESI) m/z [M+H]⁺ calcd. for C₂₂H₂₆FN₆O₂S 457.1822; found 457.1817.

5-((4-((2,4-Difluoro-3-methoxybenzyl)oxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)pyridin-2-amine[158]

158 was obtained in 95% yield following the general procedure above. ¹HNMR (500 MHz, CDCl₃) δ 8.21 (s, 1H), 8.10 (s, 1H), 7.40 (dd, J=8.5, 2.2Hz, 1H), 6.80-6.91 (m, 2H), 6.35 (d, J=8.5 Hz, 1H), 5.38 (s, 2H), 4.49(br s, 2H), 4.00 (s, 3H), 3.85 (m, 4H), 2.49-2.50 (m, 4H), 2.37 (s, 3H);HRMS (ESI) m/z [M+H]⁺ calcd. for C₂₂H₂₅F₂N₆O₂S 475.1728; found 475.1718.

Example 19

4-((4-(Benzyloxy)-2-(piperazin-1-yl)pyrimidin-5-yl)thio)benzonitrile[166]

A mixture of 162 (75 mg, 0.189 mmol), K₂CO₃ (52.2 mg, 0.378 mmol),neocuproine (11.8 mg, 0.0567 mmol), CuI (10.8 mg, 0.0567 mmol) and4-mercaptobenzonitrile (31.9 mg, 0.236 mmol) in DMF (2 mL) was heated at120° C. for 20 h. Solvent was removed under reduced pressure and theresidue was purified by preparatory TLC (CH₂Cl₂:MeOH—NH₃ (7 N), 15:1) toafford 24.6 mg (32%) of 166. ¹H NMR (500 MHz, CDCl₃): δ 8.17 (s, 1H),7.34 (d, J=8.3 Hz, 2H), 7.15-7.21 (m, 3H), 7.05-7.09 (m, 2H), 7.02 (d,J=8.3 Hz, 2H), 5.29 (s, 2H), 3.74-3.80 (m, 4H), 2.84-2.89 (m, 4H); ¹³CNMR (125 MHz, CDCl₃): δ 168.6, 165.1, 161.8, 145.7, 136.3, 132.1, 128.4,128.0, 127.5, 126.1, 119.0, 108.2, 96.7, 67.8, 45.9, 45.2; HRMS (ESI)m/z [M+H]⁺ calcd. for C₂₂H₂₂N₅OS, 404.1545; found 404.1537.

4-((4-(Benzyloxy)-2-(piperazin-1-yl)pyrimidin-5-yl)thio)benzamide [167]

A mixture of 166 (18.5 mg, 0.0458 mmol) and KOH (56.5 mg, 1.01 mmol) int-BuOH (500 μL) was heated at 80° C. for 1 h. Solvent was removed underreduced pressure and the residue was purified by preparatory TLC(CH₂Cl₂:MeOH—NH₃ (7 N), 15:1) to afford 15 mg (78%) of 167. ¹H NMR (500MHz, CDCl₃): δ 8.26 (s, 1H), 7.62 (d, J=8.3 Hz, 2H), 7.21-7.25 (m, 3H),7.10-7.16 (m, 4H), 5.97 (br s, 1H), 5.80 (br s, 1H), 5.36 (s, 2H),3.80-3.87 (m, 4H), 2.90-2.97 (m, 4H); ¹³C NMR (125 MHz, CDCl₃): δ 168.8,168.6, 164.9, 161.7, 143.7, 136.4, 129.9, 128.3, 127.8, 127.7, 127.4,126.1, 97.9, 67.8, 45.9, 45.1; HRMS (ESI) m/z [M+H]⁺ calcd. forC₂₂H₂₄N₅O₂S, 422.1651; found 422.1644.

4-((2-(4-Acetylpiperazin-1-yl)-4-(benzyloxy)pyrimidin-5-yl)thio)benzamide[168]

A solution of 167 (10 mg, 0.023 mmol) and DMAP (0.001 mmol, 2 mg) in 2mL of acetic anhydride was stirred at 110° C. for 2 h. Solvent wasremoved under reduced pressure and the residue was purified bypreparatory TLC (CH₂Cl₂: hexane: EtOAc: MeOH—NH₃ (7 N), 4:4:2:1) toyield 6.8 mg (61%) of 168. ¹H NMR (600 MHz, CDCl₃): δ 8.21 (s, 1H), 7.62(d, J=8.6 Hz, 2H), 7.17-7.20 (m, 3H), 7.05-7.07 (m, 4H), 5.95 (br s,1H), 5.75 (br s, 1H), 5.29 (s, 2H), 3.80-3.83 (m, 2H), 3.76-3.83 (m,2H), 3.61-3.63 (m, 4H), 3.45-3.48 (m, 2H), 2.09 (s, 3H); ¹³C NMR (150MHz, CDCl₃): δ 169.3, 168.7, 168.6, 164.8, 161.5, 143.3, 136.2, 130.0,128.4, 127.9, 127.8, 127.3, 126.2, 99.0, 68.0, 45.9, 43.7, 41.1. HRMS(ESI) m/z [M+H]⁺ calcd. for C₂₄H₂₆N₅O₂S, 464.1721; found 464.1728.

Example 20

4-((2,4-Dihydroxypyrimidin-5-yl)thio)benzonitrile [175]

A mixture of 5-iodopyrimidine-2,4-diol 174 (1 g, 4.2 mmol),4-mercaptobenzonitrile (0.68 g, 5.04 mmol) and K₂CO₃ (1.74 g, 12.6 mmol)in DMF (30 mL) was evacuated and backfilled with argon three times.Copper(I)thiophene-2-carboxylate (0.32 g, 1.68 mmol) was added andevacuated and backfilled with argon two times and the reaction mixturewas heated at 130° C. for 16 h. Solvent was removed under reducedpressure and purified by column chromatography (CH₂Cl₂:CH₃OH:CH₃COOH,25:1:0.3) to give 0.65 g (63%) of 175. ¹H NMR (500 MHz, DMSO-d₆): δ 8.03(s, 1H), 7.69 (d, J=7.9 Hz, 2H), 7.31 (d, J=8.6 Hz, 2H); ¹³C NMR (125MHz, DMSO-d₆): δ 162.6, 151.6, 150.8, 144.9, 132.4, 125.7, 118.8, 107.2,99.1; HRMS (ESI) m/z [M−H]⁺ calcd. for C₁₁H6N₃O₂S, 244.0181; found244.0178.

4-((2,4-Dichloropyrimidin-5-yl)thio)benzonitrile [176]

In a 100 mL round bottomed flask containing 0.65 g (2.65 mmol) of 175was added 12.1 mL of POCl₃ (20.34 g, 132.65 mmol) with stirring. To thismixture 1.15 mL of DIEA (0.85 g, 6.63 mmol) was added slowly and thereaction was heated at 100° C. for 1 h. After cooling to rt, thereaction mixture was added to a beaker containing ice chips. Followingcomplete quenching of POCl₃, solid Na₂CO₃ was carefully added untilpH˜9. This was transferred to a seperatory funnel and extracted withCH₂Cl₂ (4×75 mL), dried over MgSO₄, filtered and concentrated to a solidwhich was purified by column chromatography (hexane:EtOAc, 80:20) toafford 0.56 g (86%) of 176. ¹H NMR (500 MHz, CDCl₃): δ 8.34 (s, 1H),7.61 (d, J=8.2 Hz, 2H), 7.34 (d, J=8.2 Hz, 2H); ¹³C NMR (125 MHz,CDCl₃): δ 163.5, 161.9, 159.9, 137.9, 133.5, 131.1, 128.8, 118.0, 112.5;MS (ESI) m/z [M+H]⁺ 282.1.

4-((4-(Benzyloxy)-2-chloropyrimidin-5-yl)thio)benzonitrile [177]

To 176 (0.16 g, 0.57 mmol) dissolved in toluene (10 mL) was addedbenzylalcohol (59 μL, 61.5 mg, 0.57 mmol). KOH (32 mg, 0.57 mmol) wasadded followed by 18-crown-6 (7.5 mg, 0.03 mmol) and reaction wasstirred at rt for 12 h. Then the reaction mixture was concentrated underreduced pressure to give a residue to which 50 mL EtOAc was added. Thiswas transferred to a seperatory funnel and washed with 0.1 N HCl (30 mL)followed by H₂O (2×30 mL), dried over MgSO₄, filtered and concentratedto a solid which was purified by column chromatography (hexane:EtOAc,90:10 to 80:20) to afford 67 mg (34%) of 177. MS (m/z): [M+H]⁺ 354.2.

4-((4-(Benzyloxy)-2-morpholinopyrimidin-5-yl)thio)benzonitrile [178a]

To 177 (15.0 mg, 0.039 mmol) was added morpholine (4.1 mg, 0.047 mmol)in DMF (2 mL) and heated at 90° C. for 2 h. Solvent was removed underreduced pressure and the residue was purified by preparatory TLC(hexane:EtOAc, 75:25) to afford 7.8 mg (45%) of 178a. MS (m/z): [M+H]⁺405.5.

(S)-4-((4-(Benzyloxy)-2-(3-(dimethylamino)pyrrolidin-1-yl)pyrimidin-5-yl)thio)benzonitrile[178c]

To 177 (10.0 mg, 0.028 mmol) was added(S)—N,N-dimethylpyrrolidin-3-amine (3.9 mg, 0.034 mmol) in DMF (2 mL)and heated at 90° C. for 2 h. Solvent was removed under reduced pressureand the residue was purified by Prep TLC (CH₂Cl₂:MeOH, 10:1) to afford5.8 mg (48%) of 178c. MS (m/z): [M+H]⁺ 432.3.

4-((4-((4-(Benzyloxy)-2-morpholinopyrimidin-5-yl)thio)benzamide [179a]

A mixture of 178a (7.8 mg, 0.019 mmol) and KOH (23.8 mg, 0.425 mmol) int-BuOH (1 mL) was heated at 80° C. for 1 h. Solvent was removed underreduced pressure and the residue was purified by preparatory TLC(hexane:EtOAc, 75:25, two times) to afford 4.7 mg (59%) of 179a. ¹H NMR(600 MHz, CDCl₃): δ 8.21 (s, 1H), 7.56 (d, J=8.5 Hz, 2H), 7.17-7.19 (m,3H), 7.04-7.06 (m, 4H), 5.91 (br s, 1H), 5.51 (br s, 1H), 5.29 (s, 2H),3.76-3.79 (m, 4H), 3.69-3.70 (m, 4H); ¹³C NMR (150 MHz, CDCl₃): δ 168.9,168.8, 165.1, 161.9, 143.8, 136.5, 130.1, 128.6, 128.1, 127.9, 127.6,126.3, 98.8, 68.1, 66.9, 44.6; HRMS (ESI) m/z [M+H]⁺ calcd. forC₂₂H₂₃N₄O₃S, 423.1491; found 423.1481.

(S)-4-((4-(Benzyloxy)-2-(3-(dimethylamino)pyrrolidin-1-yl)pyrimidin-5-yl)thio)benzamide(179c)

A mixture of 178c (5.8 mg, 0.014 mmol) and KOH (16.6 mg, 0.30 mmol) int-BuOH (1 mL) was heated at 80° C. for 1 h. Solvent was removed underreduced pressure and the residue was purified by preparatory TLC(CH₂Cl₂:MeOH—NH₃ (7 N), 10:1) to afford 4.1 mg (63%) of 179c. ¹H NMR(600 MHz, CDCl₃): δ 8.27 (s, 1H), 7.62 (d, J=8.5 Hz, 2H), 7.24 (t, J=8.5Hz, 3H), 7.16 (s, 2H), 7.11 (J=8.4 Hz, 2H), 5.98 (br s, 1H), 5.58 (br s,1H), 5.39 (s, 2H), 3.82-3.98 (m, 2H), 3.49-3.54 (m, 1H), 3.31-3.36 (m,1H), 2.78-2.82 (m, 1H), 2.34 (s, 3H), 2.32 (s, 3H), 2.20-2.25 (m, 1H),1.88-1.95 (m, 1H); ¹³C NMR (150 MHz, CDCl₃): δ 168.6, 168.5, 164.9,160.2, 143.9, 136.6, 136.5, 129.7, 128.3, 127.8, 127.7, 127.6, 125.8,97.4, 67.8, 65.4, 51.3, 46.1, 44.4, 30.4; HRMS (ESI) m/z [M+H]⁺ calcd.for C₂₄H₂₈N₅O₂S, 450.1964; found 450.1956.

Example 21

4-((4-(Benzyloxy)-2-((2R,5S)-2,5-dimethylpiperazin-1-yl)pyrimidin-5-yl)thio)benzonitrile[180]

To 177 (20 mg, 0.056 mmol) was added trans-2,5-dimethylpiperazine (8 mg,0.0672 mmol) and Et₃N (15 μl, 0.11 mmol) in DMF (3 mL) and heated at 90°C. for 2 h. Solvent was removed under reduced pressure and the residuewas purified by preparative TLC (CH₂Cl₂:MeOH, 10:1) to afford 20 mg(82%) of 180. ¹H NMR (500 MHz, CDCl₃): δ 8.24 (s, 1H), 7.42 (d, J=8.3Hz, 2H), 7.23-7.27 (m, 3H), 7.10-7.16 (m, 4H), 5.41 (d, J=12.6 Hz, 1H),5.31 (d, J=12.6 Hz, 1H), 4.76 (m, 1H), 4.29 (d, J=13.4 Hz, 1H),3.29-3.39 (m, 3H), 2.64 (d, J=13.0 Hz, 1H), 1.83-1.87 (m, 1H), 1.27 (d,J=6.5 Hz, 3H), 1.19 (d, J=6.7 Hz, 3H); MS (m/z): [M+H]⁺ 432.0.

4-((4-(Benzyloxy)-2-((2R,5S)-2,4,5-trimethylpiperazin-1-yl)pyrimidin-5-yl)thio)benzonitrile[181]

To a solution of 180 (20 mg, 0.046 mmol) in MeOH (3 mL) was addedformalin (20 μL, 0.269 mmol), sodium acetate (20 mg, 0.244 mmol) andsodium cyanoborohydride (20 mg, 0.095 mmol) and was heated at 50° C. for5 h. Solvent was removed under reduced pressure and the residue waspurified by preparative TLC (CH₂Cl₂:MeOH, 10:1) to afford 16 mg (77%) of181. MS (ESI) m/z [M+H]⁺ 446.4.

4-((4-(Benzyloxy)-2-((2R,5S)-2,4,5-trimethylpiperazin-1-yl)pyrimidin-5-yl)thio)benzamide[182]

A mixture of 181 (16 mg, 0.036 mmol) and KOH (40 mg, 0.71 mmol) int-BuOH (3 mL) was heated at 80° C. for 1 h. Solvent was removed underreduced pressure and the residue was purified by preparatory TLC(CH₂Cl₂:MeOH, 20:1) to afford 9 mg (54%) of 182. ¹H NMR (600 MHz, CDCl₃)δ 8.19 (s, 1H), 7.56 (d, J=8.4 Hz, 2H), 7.16-7.19 (m, 3H), 7.06-7.08 (m,4H), 5.95 (br s, 1H), 5.62 (br s, 1H), 5.33 (d, J=12.6 Hz, 1H), 5.22 (d,J=12.6 Hz, 1H), 4.79 (s, 1H), 4.35 (d, J=13.2 Hz, 1H), 3.38 (d, J=12.0Hz, 1H), 2.97 (s, 1H), 2.74 (dd, J=12.0, 4.6 Hz, 1H), 2.34 (d, J=10.9Hz, 1H), 2.30 (s, 3H), 1.24 (d, J=6.6 Hz, 3H), 0.88 (d, J=6.5 Hz, 3H);¹³C NMR (150 MHz, CDCl₃) δ 168.7, 168.6, 165.0, 162.1, 143.8, 136.5,129.8, 128.3, 127.8, 127.7, 127.3, 126.0, 97.4, 67.7, 54.3, 52.0, 46.9,44.0, 42.8, 15.7, 7.8; HRMS (ESI) m/z [M+H]⁺ calcd. for C₂₅H₃₀N₅O₂S464.2120; found 464.2104.

Example 22

4-((2-Chloro-4-((3-(dimethylamino)benzyl)oxy)pyrimidin-5-yl)thio)benzonitrile[183]

To 176 (0.26 g, 0.935 mmol) dissolved in toluene (12 mL) was added3-dimethylaminobenzylalcohol (134 μL, 141.0 mg, 0.935 mmol). KOH (78 mg,1.4 mmol) was added followed by 18-crown-6 (12 mg, 0.047 mmol) andreaction was stirred at rt for 12 h. Then the reaction mixture wasconcentrated under reduced pressure to give a residue to which 100 mLEtOAc was added. This was transferred to a seperatory funnel and washedwith 0.1 N HCl (50 mL) followed by H₂O (2×50 mL), dried over MgSO₄,filtered and concentrated to a solid which was purified by columnchromatography (hexane:EtOAc, 90:10 to 80:20) to afford 0.11 g (30%) of183. ¹H NMR (500 MHz, CDCl₃): δ 8.36 (s, 1H), 7.35 (d, J=8.4 Hz, 2H),7.09 (t, J=8.0 Hz, 1H), 7.07 (d, J=8.4 Hz, 2H), 6.61 (dd, J=8.6, 2.3 Hz,1H), 6.52 (s, 1H), 6.42 (d, J=7.3 Hz, 1H), 5.32 (s, 2H), 2.84 (s, 6H);MS (ESI) m/z [M+H]⁺ 397.2.

4-((4-((3-(Dimethylamino)benzyl)oxy)-2-morpholinopyrimidin-5-yl)thio)benzonitrile[184a]

To 183 (10.0 mg, 0.0252 mmol) was added morpholine (2.64 mg, 0.0303mmol) in DMF (2 mL) and heated at 90° C. for 2 h. Solvent was removedunder reduced pressure and the residue was purified by preparatory TLC(hexane:EtOAc, 7:3) to afford 6.2 mg (64%) of 184a. MS (m/z): [M+H]⁺448.3.

4-((4-((3-(Dimethylamino)benzyl)oxy)-2-(4-isopropylpiperazin-1-yl)pyrimidin-5-yl)thio)benzonitrile[184b]

To 183 (10.0 mg, 0.0252 mmol) was added N-isopropylpiperazine (4.2 mg,0.033 mmol) in DMF (2 mL) and heated at 90° C. for 2 h. Solvent wasremoved under reduced pressure and the residue was used in the next stepwithout further purification. MS (m/z): [M+H]⁺ 489.4.

4-((4-((3-(Dimethylamino)benzyl)oxy)-2-(4-(2-hydroxyethyl)piperazin-1-yl)pyrimidin-5-yl)thio)benzonitrile[184d]

To 183 (10.0 mg, 0.0252 mmol) was added 2-(piperazin-1-yl)ethanol (4.3mg, 0.033 mmol) in DMF (2 mL) and heated at 90° C. for 2 h. Solvent wasremoved under reduced pressure and the residue was used in the next stepwithout further purification. MS (m/z): [M+H]⁺ 491.4.

4-((4-((3-(Dimethylamino)benzyl)oxy)-2-(4-(hex-5-yn-1-yl)piperazin-1-yl)pyrimidin-5-yl)thio)benzonitrile[184e]

To 183 (10.0 mg, 0.0252 mmol) was added 1-(hex-5-yn-1-yl)piperazine (5.5mg, 0.033 mmol) and Et₃N (100 μL) in DMF (2 mL) and was stirred at rtfor overnight. Solvent was removed under reduced pressure and theresidue was used in the next step without further purification. ¹H NMR(500 MHz, CDCl₃) δ 8.22 (s, 1H), 7.39 (d, J=8.5 Hz, 2H), 7.13 (t, J=7.8Hz, 1H), 7.06 (d, J=8.5 Hz, 2H), 6.63 (dd, J=8.3, 2.2 Hz, 1H), 6.50-6.56(m, 2H), 5.33 (s, 2H), 3.90 (m, 4H), 2.84 (s, 6H), 2.52 (m, 4H), 2.42(t, J=7.0 Hz, 2H), 2.25 (td, J=7.0, 2.6 Hz, 2H), 1.97 (t, J=2.5 Hz, 1H),1.66-1.71 (m, 2H), 1.57-1.62 (m, 2H); MS (m/z): [M+H]⁺ 527.1.

4-((4-((3-(Dimethylamino)benzyl)oxy)-2-morpholinopyrimidin-5-yl)thio)benzamide[185a]

A mixture of 184a (6.2 mg, 0.014 mmol) and KOH (17.1 mg, 0.305 mmol) int-BuOH (1 mL) was heated at 80° C. for 1 h. Solvent was removed underreduced pressure and the residue was purified by preparatory TLC(hexane:EtOAc, 1:1) to afford 4.1 mg (63%) of 185a. ¹H NMR (600 MHz,CDCl₃): δ 8.19 (s, 1H), 7.53 (d, J=8.4 Hz, 2H), 7.05 (t, J=8.4 Hz, 1H),7.02 (d, J=8.4 Hz, 2H), 6.56 (dd, J=8.9, 2.6 Hz, 1H), 6.50 (s, 1H), 6.46(d, J=7.4 Hz, 1H), 5.97 (br s, 1H), 5.49 (br s, 1H), 5.27 (s, 2H),3.78-3.79 (m, 4H), 3.69-3.71 (m, 4H), 2.75 (s, 6H); ¹³C NMR (150 MHz,CDCl₃): δ 168.9, 168.6, 164.9, 161.8, 150.6, 143.6, 137.1, 129.7, 129.0,127.7, 125.7, 115.7, 112.1, 111.6, 98.2, 68.4, 66.7, 44.4, 40.5; HRMS(ESI) m/z [M+H]⁺ calcd. for C₂₄H₂₅N₅O₃S, 466.1913; found 466.1901.

4-((4-((3-(Dimethylamino)benzyl)oxy)-2-(4-isopropylpiperazin-1-yl)pyrimidin-5-yl)thio)benzamide[185b]

A mixture of 184b and KOH (31.0 mg, 0.055 mmol) in t-BuOH (1.5 mL) washeated at 80° C. for 1 h. Solvent was removed under reduced pressure andthe residue was purified by preparatory TLC (CH₂Cl₂: MeOH—NH₃ (7 N),10:1) to afford 9.2 mg (72%) of 185b. ¹H NMR (600 MHz, CDCl₃): δ 8.17(s, 1H), 7.52 (d, J=10.0 Hz, 2H), 7.04 (t, J=9.6 Hz, 1H), 7.01 (d,J=10.4 Hz, 2H), 6.55 (dd, J=10.0, 2.9 Hz, 1H), 6.51 (s, 1H), 6.47 (d,J=9.2 Hz, 1H), 5.95 (br s, 1H), 5.47 (br s, 1H), 5.26 (s, 2H), 3.82-3.84(m, 4H), 2.74 (s, 6H), 2.66-2.70 (m, 1H), 2.52-2.54 (m, 4H), 1.02 (d,J=7.9 Hz, 6H); ¹³C NMR (150 MHz, CDCl₃): δ 168.9, 168.8, 164.9, 161.6,150.6, 143.8, 137.1, 129.7, 128.9, 127.7, 125.7, 115.8, 112.1, 111.7,97.6, 68.3, 54.7, 48.5, 44.2, 40.5, 18.4; HRMS (ESI) m/z [M+H]⁺ calcd.for C₂₇H₃₅N₆O₂S, 507.2542; found 507.2543.

4-((4-((3-(Dimethylamino)benzyl)oxy)-2-(4-(2-hydroxyethyl)piperazin-1-yl)pyrimidin-5-yl)thio)benzamide[185d]

A mixture of 184d and KOH (31.0 mg, 0.055 mmol) in t-BuOH (1.5 mL) washeated at 80° C. for 1 h. Solvent was removed under reduced pressure andthe residue was purified by preparatory TLC (CH₂Cl₂: MeOH—NH₃ (7 N),10:1) to afford 10.2 mg (80%) of 185d. ¹H NMR (600 MHz, CDCl₃): δ 8.18(s, 1H), 7.53 (d, J=8.5 Hz, 2H), 7.05 (t, J=7.5 Hz, 1H), 7.02 (d, J=8.5Hz, 2H), 6.56 (dd, J=8.5, 2.3 Hz, 1H), 6.51 (s, 1H), 6.47 (d, J=7.6 Hz,1H), 5.26 (s, 2H), 3.83-3.84 (m, 4H), 3.62-3.63 (m, 4H), 2.74 (s, 6H),2.53-2.57 (m, 6H); ¹³C NMR (150 MHz, CDCl₃): δ 169.1, 168.9, 164.9,161.6, 150.6, 143.7, 137.1, 129.7, 128.9, 127.7, 125.7, 115.8, 112.2,111.7, 97.9, 68.4, 59.6, 57.7, 43.8, 40.5; HRMS (ESI) m/z [M+H]⁺ calcd.for C₂₆H₃₃N₆O₃S, 509.2335; found 509.2336.

4-((4-((3-(Dimethylamino)benzyl)oxy)-2-(4-(hex-5-yn-1-yl)piperazin-1-yl)pyrimidin-5-yl)thio)benzamide[185e]

A mixture of 184e (12 mg, 0.023 mmol) and KOH (28 mg, 0.5 mmol) int-BuOH (2 mL) was heated at 80° C. for 1 h. Solvent was removed underreduced pressure and the residue was purified by preparatory TLC(CH₂Cl₂: MeOH—NH₃ (7 N), 10:1) to afford 5.7 mg (46%) of 185e. ¹H NMR(600 MHz, CDCl₃) δ 8.25 (s, 1H), 7.59 (d, J=8.4 Hz, 2H), 7.12 (t, J=7.9Hz, 1H), 7.07 (d, J=8.4 Hz, 2H), 6.61-6.63 (m, 1H), 6.57 (s, 1H), 6.54(d, J=7.5 Hz, 1H), 6.09 (br s, 1H), 5.68 (br s, 1H), 5.34 (s, 2H), 3.90(m, 4H), 2.81 (s, 6H), 2.53 (m, 4H), 2.40-2.45 (m, 2H), 2.25 (td, J=7.0,2.6 Hz, 2H), 1.98 (t, J=2.6 Hz, 1H), 1.64-1.71 (m, 2H), 1.55-1.63 (m,2H); ¹³C NMR (150 MHz, CDCl₃) δ 168.8, 165.0, 161.6, 150.5, 143.8,137.1, 129.5, 129.0, 127.7, 125.5, 115.8, 112.0, 111.6, 97.4, 84.2,68.6, 68.2, 58.0, 52.9, 43.8, 40.5, 26.3, 25.8, 18.3; HRMS (ESI) m/z[M+H]⁺ calcd. for C₃₀H₃₇N₆O₂S 545.2699; found 545.2701.

Example 23

tert-Butyl3-(5-((4-cyanophenyl)thio)-4-((3-(dimethylamino)benzyl)oxy)pyrimidin-2-yl)-1H-pyrrole-1-carboxylate[186]

To a solution of 183 (20 mg, 0.038 mmol) in DMF (2 mL) in a roundbottomed flask, was added tert-butyl3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-1-carboxylate(18.0 mg, 0.076 mmol) followed by NaHCO₃ (9.5 mg, 0.113 mmol). Thenvacuum was applied to the reaction mixture followed by back filling theflask with argon. This vacuum-argon cycle was performed for two moretimes. Then PdCl₂(PPh₃)₂ (5.3 mg, 0.0076 mmol), and 0.1 mL of degasseddistilled H₂O were added to the reaction mixture. The reaction mixturewas then subjected to vacuum-argon cycle for two more times and heatedat 90° C. for 16 h. Solvent was removed under reduced pressure and theresulting residue was purified by preparatory TLC (hexane: EtOAc, 8:2)to give 10 mg (71%) of 186. MS (m/z): [M+H]⁺ 528.1.

4-((4-((3-(Dimethylamino)benzyl)oxy)-2-(1H-pyrrol-3-yl)pyrimidin-5-yl)thio)benzamide[187]

To 186 (10 mg, 0.019 mmol) dissolved in CH₂C₂ (2 mL) was added 140 μL ofTFA and the reaction mixture was stirred at rt for 20 h. Solvent wasremoved under reduced pressure to get residue (MS (m/z): [M+H]⁺ 428.20)and t-BuOH (1 mL) was added followed by KOH (20 mg, 0.36 mmol) and thereaction mixture was heated at 80° C. for 1 h. Solvent was removed underreduced pressure and the residue was purified by preparatory TLC(CH₂Cl₂:MeOH—NH₃ (7 N), 10:1) to afford 5.3 mg (61%) of 187. ¹H NMR (600MHz, CDCl₃): δ 8.75 (s, 1H), 7.70-7.71 (m, 1H), 7.60 (d, J=8.5 Hz, 2H),7.14 (d, J=8.5 Hz, 2H), 7.13 (t, J=9.1 Hz, 1H), 6.97-6.98 (m, 1H),6.85-6.86 (m, 1H), 6.66 (s, 1H), 6.64 (dd, J=9.1, 2.2 Hz, 1H), 6.61 (d,J=9.1, 2.2 Hz, 1H), 5.49 (s, 2H), 2.84 (s, 6H); ¹³C NMR (150 MHz,CDCl₃): δ 173.5, 168.9, 167.9, 163.6, 162.6, 150.6, 141.4, 136.8, 129.1,127.8, 127.1, 123.9, 121.5, 119.2, 116.4, 112.4, 112.3, 108.9, 108.5,68.7, 40.6; HRMS (ESI) m/z [M+H]⁺ calcd. for C₂₄H₂₄N₅O₂S, 446.1651;found 446.1647.

Example 24

4-((2-Chloro-4-((3-methoxybenzyl)oxy)pyrimidin-5-yl)thio)benzonitrile[188]

To 176 (0.3 g, 1.07 mmol) dissolved in toluene (18 mL) was added3-methoxybenzylalcohol (133 μL, 147.3 mg, 1.07 mmol). KOH (68 mg, 1.28mmol) was added followed by 18-crown-6 (14.1 mg, 0.054 mmol) andreaction was stirred at rt for 12 h. Then the reaction mixture wasconcentrated under reduced pressure to give a residue to which 120 mLEtOAc was added. This was transferred to a seperatory funnel and washedwith 0.1 N HCl (60 mL) followed by H₂O (2×60 mL), dried over MgSO₄,filtered and concentrated to a solid which was purified by columnchromatography (hexane:EtOAc, 90:10 to 80:20) to afford 0.13 g (32%) of188. ¹H NMR (600 MHz, CDCl₃): δ 8.41 (s, 1H), 7.43 (d, J=8.6 Hz, 2H),7.18 (t, J=8.2 Hz, 1H), 7.16 (d, J=8.6 Hz, 2H), 6.82 (dd, J=8.2, 1.8 Hz,1H), 6.70 (d, J=7.7 Hz, 1H), 6.62 (s, 1H), 5.36 (s, 2H), 3.75 (s, 3H);¹³C NMR (150 MHz, CDCl₃): δ 168.6, 162.7, 160.8, 159.7, 140.7, 135.9,132.7, 129.7, 128.8, 120.6, 118.5, 114.4, 113.7, 113.4, 110.4, 69.9,55.3. MS (ESI) m/z [M+H]⁺ 384.2.

4-((4-((4-((3-Methoxybenzyl)oxy)-2-morpholinopyrimidin-5-yl)thio)benzonitrile[189a]

To 188 (10.0 mg, 0.026 mmol) was added morpholine (2.7 mg, 0.031 mmol)in DMF (2 mL) and heated at 90° C. for 2 h. Solvent was removed underreduced pressure and the residue was used in the next step withoutfurther purification. MS (m/z): [M+H]⁺ 435.37.

4-((2-(4-Isopropylpiperazin-1-yl)-4-((3-methoxybenzyl)oxy)pyrimidin-5-yl)thio)benzonitrile[189b]

To 188 (10.0 mg, 0.026 mmol) was added N-isopropylpiperazine (4.0 mg,0.031 mmol) in DMF (2 mL) and heated at 90° C. for 2 h. Solvent wasremoved under reduced pressure and the residue was used in the next stepwithout further purification. MS (m/z): [M+H]⁺ 476.2.

4-((2-(4-(Dimethylamino)piperidin-1-yl)-4-((3-methoxybenzyl)oxy)pyrimidin-5-yl)thio)benzonitrile[189d]

To 188 (9.0 mg, 0.023 mmol) was added N,N-dimethylpiperidin-4-amine (3.9m g, 0.03 mmol) in DMF (2 mL) and heated at 90° C. for 2 h. Solvent wasremoved under reduced pressure and and the residue was used in the nextstep without further purification. MS (m/z): [M+H]⁺ 476.2.

(R)-4-((2-(3-(Dimethylamino)pyrrolidin-1-yl)-4-((3-methoxybenzyl)oxy)pyrimidin-5-yl)thio)benzonitrile[189e]

To 188 (9.0 mg, 0.023 mmol) was added (R)—N,N-dimethylpyrrolidin-3-amine(3.4 mg, 0.03 mmol) in DMF (2 mL) and heated at 90° C. for 2 h. Solventwas removed under reduced pressure and the residue was purified bypreparatory TLC (CH₂Cl₂:MeOH, 10:1) to afford 9.7 mg (89%) of 189e. MS(m/z): [M+H]⁺ 462.1.

(S)-4-((2-(3-(Dimethylamino)pyrrolidin-1-yl)-4-((3-methoxybenzyl)oxy)pyrimidin-5-yl)thio)benzonitrile[189f]

To 188 (9.0 mg, 0.023 mmol) was added (S)—N,N-dimethylpyrrolidin-3-amine(3.4 mg, 0.03 mmol) in DMF (2 mL) and heated at 90° C. for 2 h. Solventwas removed under reduced pressure and the residue was purified byprepatory TLC (CH₂Cl₂:MeOH, 10:1) to afford 9.5 mg (88%) of 189f. MS(m/z): [M+H]⁺ 462.2.

4-((2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-((3-methoxybenzyl)oxy)pyrimidin-5-yl)thio)benzonitrile[189g]

To 188 (9.0 mg, 0.023 mmol) was addedN¹,N¹,N²-trimethylethane-1,2-diamine (3.1 mg, 0.03 mmol) in DMF (2 mL)and heated at 90° C. for 2 h. Solvent was removed under reduced pressureand the residue was purified by prepatory TLC (CH₂Cl₂:MeOH—NH₃ (7 N),20:1) to afford 7 mg (66%) of 189g. MS (m/z): [M+H]⁺ 450.2.

4-((4-((3-Methoxybenzyl)oxy)-2-(4-methyl-1,4-diazepan-1-yl)pyrimidin-5-yl)thio)benzonitrile[189h]

To 188 (9.0 mg, 0.023 mmol) was added 1-methyl-1,4-diazepane (3.9 mg,0.03 mmol) in DMF (2 mL) and heated at 90° C. for 2 h. Solvent wasremoved under reduced pressure and the residue was purified bypreparatory TLC (CH₂Cl₂:MeOH, 10:1) to afford 10.1 mg (93%) of 189h. MS(m/z): [M+H]⁺ 462.1.

4-((2-(4-(Hex-5-yn-1-yl)piperazin-1-yl)-4-((3-methoxybenzyl)oxy)pyrimidin-5-yl)thio)benzonitrile[189j]

To 188 (20 mg, 0.0521 mmol) was added 1-(hex-5-yn-1-yl)piperazine (17.3mg, 0.104 mmol) and Et₃N (100 μL, 0.72 mmol) in DMF (3 mL) and stirredat rt for overnight. Solvent was removed under reduced pressure and theresidue was purified by preparatory TLC (CH₂Cl₂:MeOH, 10:1) to afford24.6 mg (92%) of 189j. ¹H NMR (500 MHz, CDCl₃): δ 8.16 (s, 1H), 7.34 (d,J=8.6 Hz, 2H), 7.10 (t, J=7.9 Hz, 1H), 7.02 (d, J=8.6 Hz, 2H), 6.72 (dd,J=8.2, 2.5 Hz, 1H), 6.66 (d, J=7.6 Hz, 1H), 6.59 (s, 1H), 5.22 (s, 2H),3.79-3.81 (m, 4H), 3.65 (s, 3H), 2.43-2.45 (m, 4H), 2.35 (t, J=7.6 Hz,2H), 2.17 (td, J=7.0, 2.7 Hz, 2H), 1.89 (t, J=2.6 Hz, 1H), 1.60 (m, 2H),1.52 (m, 2H); MS (m/z): [M+H]⁺ 514.3.

4-((4-((3-Methoxybenzyl)oxy)-2-(4-(pent-4-yn-1-yl)piperazin-1-yl)pyrimidin-5-yl)thio)benzonitrile[189k]

To 188 (15 mg, 0.039 mmol) was added 1-(pent-4-yn-1-yl)piperazine (7.6mg, 0.05 mmol) and Et₃N (10 μL, 0.072 mmol) in DMF (3 mL) and heated at90° C. for 3 h. Solvent was removed under reduced pressure and theresidue was purified by preparatory TLC (CH₂Cl₂:MeOH, 30:1) to afford 18mg (92%) of 189k. MS (ESI) m/z [M+H]⁺ 500.3.

4-((2-(3-(Dimethylamino)azetidin-1-yl)-4-((3-methoxybenzyl)oxy)pyrimidin-5-yl)thio)benzonitrile[189m]

To 188 (10 mg, 0.026 mmol) was added N,N-dimethylazetidin-3-amine (13mg, 0.13 mmol) and Et₃N (20 μL, 0.144 mmol) in DMF (3 mL) and heated at90° C. for 3 h. Solvent was removed under reduced pressure and theresidue was purified by preparatory TLC (CH₂Cl₂:MeOH, 30:1) to afford189m in quantitative yield. ¹H NMR (500 MHz, CDCl₃): δ 8.15 (s, 1H),7.34 (d, J=8.5 Hz, 2H), 7.10 (t, J=7.9 Hz, 1H), 6.99 (d, J=8.5 Hz, 2H),6.72 (dd, J=8.2, 2.4, 1H), 6.67 (d, J=7.6 Hz, 1H), 6.61 (s, 1H), 5.26(s, 2H), 4.12 (dd, J=9.4, 8.5 Hz, 2H), 3.96 (dd, J=9.4, 7.3 Hz, 2H),3.66 (s, 3H), 3.16 (quintet, J=5.5 Hz, 1H), 2.19 (s, 6H); MS (ESI) m/z[M+H]⁺ 448.0.

4-((2-(4-(But-3-yn-2-yl)piperazin-1-yl)-4-((3-methoxybenzyl)oxy)pyrimidin-5-yl)thio)benzonitrile[189n]

To 188 (10 mg, 0.026 mmol) was added 1-(but-3-yn-2-yl)piperazine (18 mg,0.13 mmol) and Et₃N (200 μL, 1.44 mmol) in DMF (3 mL) and heated at 90°C. for 3 h. Solvent was removed under reduced pressure and the residuewas purified by preparatory TLC (CH₂Cl₂:MeOH, 30:1) to afford 12 mg(94%) of 189n. ¹H NMR (500 MHz, CDCl₃): δ 8.24 (s, 1H), 7.42 (d, J=8.5Hz, 2H), 7.18 (t, J=7.9 Hz, 1H), 7.10 (d, J=8.5 Hz, 2H), 6.80 (dd,J=8.3, 2.4, 1H), 6.74 (d, J=7.6 Hz, 1H), 6.67 (m, 1H), 5.34 (s, 2H),3.86-3.95 (m, 4H), 3.72 (s, 3H), 3.55-3.60 (m, 1H), 2.71-2.76 (m, 2H),2.53-2.57 (m, 2H), 2.29 (d, J=2.1 Hz, 1H), 1.41 (d, J=7.1 Hz, 3H); MS(ESI) m/z [M+H]⁺ 486.3.

4-((2-(4-Allylpiperazin-1-yl)-4-((3-methoxybenzyl)oxy)pyrimidin-5-yl)thio)benzonitrile[189o]

To 188 (10 mg, 0.026 mmol) was added 1-allylpiperazine (16.4 mg, 0.13mmol) and Et₃N (200 μL, 1.44 mmol) in DMF (3 mL) and heated at 90° C.for 3 h. Solvent was removed under reduced pressure and the residue waspurified by preparatory TLC (CH₂Cl₂:MeOH, 30:1) to afford 11 mg (89%) of189o. ¹H NMR (500 MHz, CDCl₃): δ 8.24 (s, 1H), 7.42 (d, J=8.4 Hz, 2H),7.17 (t, J=7.9 Hz, 1H), 7.09 (d, J=8.4 Hz, 2H), 6.79 (dd, J=8.2, 2.2 Hz,1H), 6.73 (d, J=7.5 Hz, 1H), 6.67 (m, 1H), 5.86-5.93 (m, 1H), 5.33 (s,2H), 5.17-5.22 (m, 2H), 3.88-3.90 (m, 4H), 3.72 (s, 3H), 3.05 (d, J=6.6Hz, 2H), 2.50-2.53 (m, 4H); MS (ESI) m/z [M+H]⁺ 474.1.

4-((2-(4-Cyclopropylpiperazin-1-yl)-4-((3-methoxybenzyl)oxy)pyrimidin-5-yl)thio)benzonitrile [189p]

To 188 (10 mg, 0.026 mmol) was added 1-cyclopropylpiperazinedihydrochloride (26 mg, 0.130 mmol), DMF (1 mL) and Et₃N (50 μL, 0.358mmol) and the reaction mixture was heated at 90° C. for 2 h. Solvent wasremoved under reduced pressure and the residue was purified bypreparatory TLC (hexane:EtOAc, 1:1) to afford 12 mg (97%) of 189p. MS(m/z): [M+H]⁺ 474.2.

4-((2-(4-(Cyclopropylmethyl)piperazin-1-yl)-4-((3-methoxybenzyl)oxy)pyrimidin-5-yl)thio)benzonitrile[189q]

To 188 (10 mg, 0.026 mmol) in DMF (1 mL) was added1-(cyclopropylmethyl)piperazine (19.3 μL, 0.130 mmol) and the reactionmixture was heated at 90° C. for 2 h. Solvent was removed under reducedpressure and the residue was purified by preparatory TLC(CH₂Cl₂:MeOH—NH₃ (7 N), 20:1) to afford 9.6 mg (76%) of 189q. MS (m/z):[M+H]⁺ 488.3.

4-((4-((3-Methoxybenzyl)oxy)-2-(4-(oxetan-3-yl)piperazin-1-yl)pyrimidin-5-yl)thio)benzonitrile [189r]

To 188 (14 mg, 0.036 mmol) in DMF (1 mL) was added1-(oxetan-3-yl)piperazine ditrifluoroacetate (184 mg, 0.50 mmol), andlastly Et₃N (50 μL, 0.358 mmol) and the reaction mixture was heated at90° C. for 4 h. The solvent was removed under reduced pressure and theresidue was purified by preparatory TLC (CH₂Cl₂:MeOH—NH₃ (7 N), 40:1) toafford 10 mg (57%) of 189r. MS (m/z): [M+H]⁺ 490.0.

4-((4-((3-Methoxybenzyl)oxy)-2-(3,3,4-trimethylpiperazin-1-yl)pyrimidin-5-yl)thio)benzonitrile [189s]

To 188 (10 mg, 0.026 mmol), 1,2,2-trimethylpiperazine (67 mg, 0.52 mmol)was added DMF (1 mL) and the reaction mixture was heated at 90° C. for 2h. Solvent was removed under reduced pressure and the residue waspurified by preparatory TLC (CH₂Cl₂:MeOH—NH₃ (7 N), 20:1) to afford 7.4mg (60%) of 189s. MS (m/z): [M+H]⁺ 476.2.

4-((4-((3-Methoxybenzyl)oxy)-2-(4-methyl-3-oxopiperazin-1-yl)pyrimidin-5-yl)thio)benzonitrile [189t]

To 188 (10 mg, 0.026 mmol) in DMF (800 μL) was added1-methylpiperazin-2-one (14.8 mg, 0.130 mmol) and the reaction mixturewas heated at 90° C. for 2 h. Solvent was removed under reduced pressureand the residue was purified by preparatory TLC (CH₂Cl₂:MeOH—NH₃ (7 N),20:1) to afford 10 mg (83%) of 189t. MS (m/z): [M+H]⁺ 462.1.

4-((2-(4-(Furan-2-ylmethyl)piperazin-1-yl)-4-((3-methoxybenzyl)oxy)pyrimidin-5-yl)thio)benzonitrile[189u]

To 188 (10 mg, 0.026 mmol) was added 1-(furan-2-ylmethyl)piperazineditrifluoroacetate (36.4 mg, 0.092 mmol), DMF (1 mL) and Et₃N (50 μL,0.358 mmol) and the reaction mixture was heated at 90° C. for 2 h.Solvent was removed under reduced pressure and the residue was purifiedby preparatory TLC (hexane:EtOAc, 1:1) to afford 10 mg (75%) of 189u. MS(m/z): [M+H]⁺ 514.3.

4-((4-((3-Methoxybenzyl)oxy)-2-(4-(thiazol-2-ylmethyl)piperazin-1-yl)pyrimidin-5-yl)thio)benzonitrile[189v]

To 188 (10 mg, 0.026 mmol) was added 2-(piperidin-4-ylmethyl)thiazoleditrifluoroacetate (38.6 mg, 0.094 mmol), DMF (1 mL), and Et₃N (50 μL,0.358 mmol) and the reaction mixture was heated at 90° C. for 2 h.Solvent was removed under reduced pressure and the residue was purifiedby preparatory TLC (hexane:EtOAc, 1:1) to afford 12 mg (87%) of 189v. MS(m/z): [M+H]⁺ 531.1.

4-((4-((3-Methoxybenzyl)oxy)-2-morpholinopyrimidin-5-yl)thio)benzamide[190a]

A mixture of intermediate 189a (11 mg, 0.025 mmol) and KOH (32.0 mg,0.057 mmol) in t-BuOH (1.5 mL) was heated at 80° C. for 1 h. Solvent wasremoved under reduced pressure and the residue was purified bypreparatory TLC (CH₂Cl₂: MeOH—NH₃ (7 N), 20:1) to afford 9.4 mg (80%) of190a. ¹H NMR (600 MHz, CDCl₃): δ 8.28 (s, 1H), 7.62 (d, J=8.6 Hz, 2H),7.17 (t, J=7.8 Hz, 1H), 7.10 (d, J=8.4 Hz, 2H), 6.78 (d, J=8.1 Hz, 1H),6.74 (d, J=7.6 Hz, 1H), 6.67 (s, 1H), 6.06 (br s, 1H), 5.68 (br s, 1H),5.33 (s, 2H), 3.83-3.85 (m, 4H), 3.75-3.77 (m, 4H), 3.68 (s, 3H); ¹³CNMR (150 MHz, CDCl₃): δ 168.8, 168.6, 164.8, 161.7, 159.5, 143.4, 137.8,129.9, 129.4, 127.7, 125.9, 119.7, 113.2, 113.1, 98.4, 67.7, 66.7, 55.2,44.3; HRMS (ESI) m/z [M+H]⁺ calcd. for C₂₃H₂₅N₄O₄S, 453.1597; found453.1599.

4-((2-(4-Isopropylpiperazin-1-yl)-4-((3-methoxybenzyl)oxy)pyrimidin-5-yl)thio)benzamide[190b]

A mixture of 189b and KOH (32.0 mg, 0.057 mmol) in t-BuOH (1.5 mL) washeated at 80° C. for 1 h. Solvent was removed under reduced pressure andthe residue was purified by preparatory TLC (CH₂Cl₂: MeOH—NH₃ (7 N),20:1) to afford 8.1 mg (64%) of 190b. ¹H NMR (600 MHz, CDCl₃): δ 8.26(s, 1H), 7.61 (d, J=8.3 Hz, 2H), 7.16 (t, J=7.9 Hz, 1H), 7.10 (d, J=8.4Hz, 2H), 6.78 (dd, J=8.2, 2.4 Hz, 1H), 6.75 (d, J=7.6 Hz, 1H), 6.68 (s,1H), 6.05 (br s, 1H), 5.63 (br s, 1H), 5.34 (s, 2H), 3.87-3.88 (m, 4H),3.68 (s, 3H), 2.75 (septet, J=6.4, 1H), 2.57-2.59 (m, 4H), 1.08 (d,J=6.5 Hz, 6H); ¹³C NMR (150 MHz, CDCl₃): δ 169.0, 168.8, 165.2, 161.8,159.7, 143.9, 138.1, 130.1, 129.5, 127.9, 126.0, 119.9, 113.5, 113.3,97.7, 67.8, 55.4, 54.8, 48.6, 44.5, 18.7; HRMS (ESI) m/z [M+H]⁺ calcd.for C₂₆H₃₂N₅O₃S, 494.2226; found 494.2215.

4-((2-(4-(Dimethylamino)piperidin-1-yl)-4-((3-methoxybenzyl)oxy)pyrimidin-5-yl)thio)benzamide[190d]

A mixture of intermediate 189d and KOH (26.0 mg, 0.046 mmol) in t-BuOH(1.5 mL) was heated at 80° C. for 1 h. Solvent was removed under reducedpressure and the residue was purified by preparatory TLC (CH₂Cl₂:MeOH—NH₃ (7 N), 20:1×2) to afford 5.3 mg (53%) of 190d. ¹H NMR (600 MHz,CDCl₃): δ 8.26 (s, 1H), 7.62 (d, J=8.4 Hz, 2H), 7.16 (t, J=7.9 Hz, 1H),7.11 (d, J=8.3 Hz, 2H), 6.78 (dd, J=8.3, 2.4 Hz, 1H), 6.76 (d, J=8.5 Hz,1H), 6.68 (s, 1H), 6.05 (br s, 1H), 5.57 (br s, 1H), 5.34 (s, 2H), 4.81(d, J=13.2 Hz, 2H), 3.68 (s, 3H), 2.88-2.96 (m, 2H), 2.47-2.51 (m, 1H),2.34 (s, 6H), 1.93-1.95 (m, 2H), 1.43-1.49 (m, 2H); ¹³C NMR (150 MHz,CDCl₃): δ 169.2, 168.6, 164.9, 161.4, 159.5, 143.6, 137.9, 129.8, 129.3,127.7, 125.8, 119.7, 113.2, 113.1, 97.6, 67.6, 62.5, 55.1, 43.4, 41.3,27.8; HRMS (ESI) m/z [M+H]⁺ calcd. for C₂₆H₃₂N₅O₃S, 494.2226; found494.2232.

(R)-4-((2-(3-(dimethylamino)pyrrolidin-1-yl)-4-((3-methoxybenzyl)oxy)pyrimidin-5-yl)thio)benzamide[190e]

A mixture of 189e (9.7 mg, 0.021 mmol) and KOH (24.0 mg, 0.42 mmol) int-BuOH (1 mL) was heated at 80° C. for 1 h. Solvent was removed underreduced pressure and the residue was purified by preparatory TLC(CH₂Cl₂:MeOH—NH₃ (7 N), 20:1) to afford 7.0 mg (70%) of 190e. ¹H NMR(600 MHz, CDCl₃): δ 8.27 (s, 1H), 7.61 (d, J=8.1 Hz, 2H), 7.16 (t, J=8.0Hz, 1H), 7.09 (d, J=8.0 Hz, 2H), 6.77 (dd, J=8.0, 2.0 Hz, 2H), 6.69 (s,1H), 6.05 (br s, 1H), 5.61 (br s, 1H), 5.36 (s, 2H), 3.82-3.96 (m, 2H),3.67 (s, 3H), 3.49-3.55 (m, 1H), 3.31-3.35 (m, 1H), 2.76-2.82 (m, 1H),2.34 (s, 3H), 2.33 (s, 3H), 2.21-2.24 (m, 1H), 1.88-1.95 (m, 1H); ¹³CNMR (150 MHz, CDCl₃): δ 168.8, 168.5, 164.9, 160.2, 159.5, 143.8, 138.2,129.8, 129.3, 127.7, 125.7, 119.9, 113.3, 113.2, 97.3, 67.6, 65.4, 55.2,51.3, 46.1, 44.4, 30.4; HRMS (ESI) m/z [M+H]⁺ calcd. for C₂₅H₃₀N₅O₃S,480.2069; found 480.2079.

(S)-4-((2-(3-(Dimethylamino)pyrrolidin-1-yl)-4-((3-methoxybenzyl)oxy)pyrimidin-5-yl)thio)benzamide[190f]

A mixture of 189f (9.5 mg, 0.021 mmol) and KOH (24.0 mg, 0.42 mmol) int-BuOH (1 mL) was heated at 80° C. for 1 h. Solvent was removed underreduced pressure and the residue was purified by preparatory TLC(CH₂Cl₂:MeOH—NH₃ (7 N), 20:1) to afford 6.4 mg (64%) of 190f. ¹H NMR(600 MHz, CDCl₃): δ 8.27 (s, 1H), 7.61 (d, J=8.3 Hz, 2H), 7.16 (t, J=7.9Hz, 1H), 7.09 (d, J=8.5 Hz, 2H), 6.77 (dd, J=8.1, 2.2 Hz, 2H), 6.69 (s,1H), 6.06 (br s, 1H), 5.63 (br s, 1H), 5.36 (s, 2H), 3.84-3.96 (m, 2H),3.68 (s, 3H), 3.49-3.54 (m, 1H), 3.32-3.35 (m, 1H), 2.77-2.79 (m, 1H),2.34 (s, 3H), 2.33 (s, 3H), 2.20-2.24 (m, 1H), 1.89-1.93 (m, 1H); ¹³CNMR (150 MHz, CDCl₃): δ 168.8, 168.4, 164.9, 160.2, 159.5, 143.8, 138.2,129.8, 129.3, 127.7, 125.7, 119.9, 113.3, 113.2, 97.3, 67.6, 65.5, 55.1,51.3, 46.1, 44.4, 30.4; HRMS (ESI) m/z [M+H]⁺ calcd. for C₂₅H₃₀N₅O₃S,480.2069; found 480.2063.

4-((2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-((3-methoxybenzyl)oxy)pyrimidin-5-yl)thio)benzamide[190g]

A mixture of 189g (7.0 mg, 0.018 mmol) and KOH (22.5 mg, 0.40 mmol) int-BuOH (1 mL) was heated at 80° C. for 1 h. Solvent was removed underreduced pressure and the residue was purified by preparatory TLC(CH₂Cl₂:MeOH—NH₃ (7 N), 20:1 then 15:1) to afford 4.7 mg (64%) of 190g.¹H NMR (600 MHz, CDCl₃): δ 8.26 (s, 1H), 7.63 (d, J=8.1 Hz, 2H), 7.16(t, J=7.8 Hz, 1H), 7.12 (d, J=7.8 Hz, 2H), 6.78 (dd, J=8.2, 2.3 Hz, 2H),6.67 (s, 1H), 6.07 (br s, 1H), 5.62 (br s, 1H), 5.36 (s, 2H), 3.81-3.90(m, 2H), 3.68 (s, 3H), 3.22 (s, 3H), 2.63-2.84 (m, 2H), 2.54 (s, 3H),2.38 (s, 3H); ¹³C NMR (150 MHz, CDCl₃): δ 168.9, 168.7, 165.0, 162.2,159.8, 143.8, 138.2, 130.1, 129.6, 127.9, 126.1, 119.4, 113.3, 113.2,97.9, 67.7, 56.1, 55.4, 45.4, 45.0, 36.2; HRMS (ESI) m/z [M+H]⁺ calcd.for C₂₅H₃₀N₅O₃S, 468.2069; found 468.2074.

(4-((4-((3-Methoxybenzyl)oxy)-2-(4-methyl-1,4-diazepan-1-yl)pyrimidin-5-yl)thio)benzamide[190h]

A mixture of 189h (10.1 mg, 0.022 mmol) and KOH (24.5 mg, 0.44 mmol) int-BuOH (1 mL) was heated at 80° C. for 1 h. Solvent was removed underreduced pressure and the residue was purified by preparatory TLC(CH₂Cl₂:MeOH—NH₃ (7 N), 20:1 then 15:1) to afford 6.5 mg (62%) of 190h.¹H NMR (600 MHz, CDCl₃): δ 8.18 (s, 1H), 7.61 (d, J=8.2 Hz, 2H), 7.09(t, J=7.8 Hz, 1H), 7.05 (d, J=7.5 Hz, 2H), 6.73 (dd, J=8.2, 2.4 Hz, 1H),6.67 (d, J=8.5 Hz, 1H), 6.65 (s, 1H), 5.26 (s, 2H), 3.73-3.81 (m, 4H),3.58 (s, 3H), 3.16-3.17 (m, 2H), 2.61-2.67 (m, 2H), 2.54-2.56 (m, 2H),2.28 (s, 3H); ¹³C NMR (150 MHz, CDCl₃): δ 170.0, 169.8, 166.4, 163.1,160.9, 144.4, 139.8, 131.7, 130.7, 129.3, 126.5, 120.9, 114.5, 114.1,98.2, 68.9, 58.5, 57.9, 56.0, 47.3, 47.1, 46.8, 27.8; HRMS (ESI) m/z[M+H]⁺ calcd. for C₂₅H₃₀N₅O₃S, 480.2069; found 480.2069.

4-((2-(4-(Hex-5-yn-1-yl)piperazin-1-yl)-4-((3-methoxybenzyl)oxy)pyrimidin-5-yl)thio)benzamide[190j]

A mixture of 189j (20 mg, 0.039 mmol) and KOH (48 mg, 0.86 mmol) int-BuOH (3 mL) was heated at 80° C. for 1 h. Solvent was removed underreduced pressure and the residue was purified by preparatory TLC(CH₂Cl₂:MeOH—NH₃ (7 N), 20:1) to afford 17.2 mg (83%) of 190j. ¹H NMR(500 MHz, CDCl₃) δ 8.26 (s, 1H), 7.61 (d, J=8.5 Hz, 2H), 7.17 (t, J=7.9Hz, 1H), 7.09 (d, J=8.5 Hz, 2H), 6.77 (dd, J=8.2, 2.5 Hz, 1H), 6.75 (d,J=7.6 Hz, 1H), 6.67 (s, 1H), 6.15 (br s, 1H), 5.93 (br s, 1H), 5.33 (s,2H), 3.88 (m, 4H), 3.67 (s, 3H), 2.52 (m, 4H), 2.40-2.43 (m, 2H), 2.25(td, J=7.2, 2.6 Hz, 2H), 1.98 (t, J=2.6 Hz, 1H), 1.63-1.71 (m, 2H),1.57-1.61 (m, 2H); ¹³C NMR (125 MHz, CDCl₃) δ 169.1, 168.7, 165.1,161.7, 159.6, 143.7, 138.0, 130.0, 129.5, 127.9, 125.9, 119.9, 113.4,113.3, 97.8, 84.4, 68.8, 67.8, 58.2, 55.3, 53.1, 44.0, 26.5, 26.0, 18.5;HRMS (ESI) m/z [M+H]⁺ calcd. for C₂₉H₃₄N₅O₃S 532.2382; found 532.2366.

4-((4-((3-Methoxybenzyl)oxy)-2-(4-(pent-4-yn-1-yl)piperazin-1-yl)pyrimidin-5-yl)thio)benzamide[190k]

A mixture of 189k (18 mg, 0.0360 mmol) and KOH (44 mg, 0.792 mmol) int-BuOH (3 mL) was heated at 80° C. for 1 h. Solvent was removed underreduced pressure and the residue was purified by preparatory TLC(CH₂Cl₂:MeOH—NH₃ (7 N), 20:1) to afford 12.4 mg (67%) of 190k. ¹H NMR(500 MHz, CDCl₃) δ 8.27 (s, 1H), 7.62 (d, J=8.5 Hz, 2H), 7.17 (t, J=7.9Hz, 1H), 7.11 (d, J=8.5 Hz, 2H), 6.78 (dd, J=8.3, 2.4 Hz, 1H), 6.75 (d,J=7.6 Hz, 1H), 6.69 (s, 1H), 6.05 (br s, 1H), 5.68 (br s, 1H), 5.34 (s,2H), 3.91 (m, 4H), 3.69 (s, 3H), 2.56 (m, 6H), 2.30 (td, J=7.0, 2.5 Hz,2H), 1.98 (t, J=2.6 Hz, 1H), 1.80 (m, 2H); ¹³C NMR (125 MHz, CDCl₃) δ169.0, 168.8, 165.1, 161.8, 159.8, 143.7, 138.1, 130.2, 129.6, 128.0,126.1, 120.0, 113.5, 113.4, 84.0, 69.0, 67.9, 57.4, 55.4, 53.6, 53.1,43.9, 16.6; HRMS (ESI) m/z [M+H]⁺ calcd. for C₂₈H₃₂N₅O₃S 518.2226; found518.2233.

4-((2-(3-(Dimethylamino)azetidin-1-yl)-4-((3-methoxybenzyl)oxy)pyrimidin-5-yl)thio)benzamide[190m]

A mixture of 189m (11.5 mg, 0.026 mmol) and KOH (32 mg, 0.57 mmol) int-BuOH (2 mL) was heated at 80° C. for 1 h. Solvent was removed underreduced pressure and the residue was purified by preparatory TLC(CH₂Cl₂:MeOH—NH₃ (7 N), 20:1) to afford 7.1 mg (59%) of 190m. ¹H NMR(600 MHz, CDCl₃) δ 8.25 (s, 1H), 7.61 (d, J=8.5 Hz, 2H), 7.17 (t, J=7.9Hz, 1H), 7.07 (d, J=8.5 Hz, 2H), 6.74-6.81 (m, 2H), 6.69 (s, 1H), 6.10(br s, 1H), 5.71 (br s, 1H), 5.34 (s, 2H), 4.19-4.23 (m, 2H), 4.04-4.07(m, 2H), 3.69 (s, 3H), 3.27 (m, 1H), 2.28 (s, 6H); ¹³C NMR (150 MHz,CDCl₃) δ 169.03, 168.98, 165.1, 162.7, 159.7, 143.6, 138.0, 130.1,129.5, 128.0, 126.0, 120.3, 113.7, 113.5, 98.8, 67.9, 56.0, 55.4, 54.3,42.0; HRMS (ESI) m/z [M+H]⁺ calcd. for C₂₄H₂₈N₅O₃S 466.1913; found466.1927.

4-((2-(4-(But-3-yn-2-yl)piperazin-1-yl)-4-((3-methoxybenzyl)oxy)pyrimidin-5-yl)thio)benzamide[190n]

A mixture of 189n (12 mg, 0.025 mmol) and KOH (30 mg, 0.54 mmol) int-BuOH (2 mL) was heated at 80° C. for 1 h. Solvent was removed underreduced pressure and the residue was purified by preparatory TLC(CH₂Cl₂:MeOH—NH₃ (7 N), 20:1) to afford 8.6 mg (68%) of 190n. ¹H NMR(600 MHz, CDCl₃) δ 8.27 (s, 1H), 7.62 (d, J=8.5 Hz, 2H), 7.17 (t, J=7.9Hz, 1H), 7.11 (d, J=8.5 Hz, 2H), 6.77-6.80 (m, 1H), 6.75 (d, J=7.5 Hz,1H), 6.68 (s, 1H), 6.06 (br s, 1H), 5.68 (br s, 1H), 5.34 (s, 2H),3.85-3.96 (m, 4H), 3.68 (s, 3H), 3.55-3.61 (m, 1H), 2.70-2.77 (m, 2H),2.52-2.59 (m, 2H), 2.29 (d, J=2.2 Hz, 1H), 1.40 (d, J=7.0 Hz, 3H); ¹³CNMR (150 MHz, CDCl₃) δ 168.8, 168.6, 164.9, 161.5, 159.5, 143.6, 137.9,129.9, 129.3, 127.7, 125.8, 119.8, 113.3, 113.1, 97.7, 81.8, 73.1, 67.6,55.1, 51.8, 48.7, 43.9, 19.1; HRMS (ESI) m/z [M+H]⁺ calcd. forC₂₇H₃₀N₅O₃S 504.2069; found 504.2090.

4-((2-(4-Allylpiperazin-1-yl)-4-((3-methoxybenzyl)oxy)pyrimidin-5-yl)thio)benzamide[190o]

A mixture of 189o (11 mg, 0.023 mmol) and KOH (28.3 mg, 0.51 mmol) int-BuOH (2 mL) was heated at 80° C. for 1 h. Solvent was removed underreduced pressure and the residue was purified by preparatory TLC(CH₂Cl₂:MeOH—NH₃ (7 N), 20:1) to afford 10.2 mg (90%) of 190o. ¹H NMR(500 MHz, CDCl₃) δ 8.26 (s, 1H), 7.61 (d, J=8.4 Hz, 2H), 7.16 (t, J=7.9Hz, 1H), 7.10 (d, J=8.4 Hz, 2H), 6.74-6.80 (m, 2H), 6.68 (s, 1H), 6.05(br s, 1H), 5.85-5.95 (m, 1H), 5.74 (br s, 1H), 5.33 (s, 2H), 5.19-5.24(m, 2H), 3.87-3.89 (m, 4H), 3.68 (s, 3H), 3.05 (d, J=6.5 Hz, 2H),2.51-2.53 (m, 4H); ¹³C NMR (125 MHz, CDCl₃) δ 168.8, 168.6, 164.9,161.6, 159.6, 143.6, 137.9, 134.6, 130.0, 129.3, 127.7, 125.9, 119.8,118.5, 113.3, 113.1, 97.8, 67.6, 61.8, 55.2, 52.8, 43.9; HRMS (ESI) m/z[M+H]⁺ calcd. for C₂₆H₃₀N₅O₃S 492.2069; found 492.2052.

4-((2-(4-Cyclopropylpiperazin-1-yl)-4-((3-methoxybenzyl)oxy)pyrimidin-5-yl)thio)benzamide [190p]

A mixture of 189p (12 mg, 0.025 mmol) and KOH (28.4 mg, 0.50 mmol) int-BuOH (2 mL) was heated at 80° C. for 1 h. Solvent was removed underreduced pressure and the residue was purified by preparatory TLC(CH₂Cl₂:MeOH—NH₃ (7 N), 20:1) to afford 8.2 mg (67%) of 190p. ¹H NMR(600 MHz, CDCl₃): δ 8.26 (s, 1H), 7.62 (d, J=8.5 Hz, 2H), 7.16 (t, J=7.9Hz, 1H), 7.11 (d, J=8.5 Hz, 2H), 6.78 (dd, J=8.2, 2.4 Hz, 1H), 6.76 (d,J=7.6 Hz, 1H), 6.68 (s, 1H), 6.05 (br s, 1H), 5.57 (br s, 1H), 5.34 (s,2H), 3.83 (m, 4H), 3.68 (s, 3H), 2.67 (m, 4H), 1.65 (m, 1H), 0.48-0.52(m, 4H); ¹³C NMR (150 MHz, CDCl₃): δ 168.7, 168.5, 164.9, 161.6, 159.5,143.6, 137.9, 129.8, 129.3, 127.7, 125.8, 119.7, 113.2, 113.1, 97.6,67.6, 55.1, 53.1, 43.9, 38.5, 5.9; HRMS (ESI) m/z [M+H]⁺ calcd. forC₂₆H₃₀N₅O₃S, 492.2069; found 492.2051.

4-((2-(4-(Cyclopropylmethyl)piperazin-1-yl)-4-((3-methoxybenzyl)oxy)pyrimidin-5-yl)thio)benzamide[190q]

A mixture of 189q (9.6 mg, 0.0196 mmol) and KOH (22 mg, 0.392 mmol) int-BuOH (2 mL) was heated at 80° C. for 2 h. Solvent was removed underreduced pressure and the residue was purified by preparatory TLC(CH₂Cl₂:MeOH—NH₃ (7 N), 20:1) to afford 8.0 mg (81%) of 190q. ¹H NMR(600 MHz, CDCl₃): δ 8.26 (s, 1H), 7.62 (d, J=8.5 Hz, 2H), 7.16 (t, J=7.9Hz, 1H), 7.11 (d, J=8.5 Hz, 2H), 6.78 (dd, J=8.2, 2.3 Hz, 1H), 6.76 (d,J=7.6 Hz, 1H), 6.68 (s, 1H), 6.03 (br s, 1H), 5.57 (br s, 1H), 5.33 (s,2H), 3.91 (m, 4H), 3.68 (s, 3H), 2.61 (m, 4H), 2.33 (m, 2H), 0.92 (m,1H), 0.56 (m, 2H), 0.15 (m, 2H); ¹³C NMR (150 MHz, CDCl₃): δ 168.7,168.5, 164.9, 161.5, 159.5, 143.5, 137.8, 129.8, 129.3, 127.7, 125.8,119.7, 113.2, 113.1, 97.7, 67.6, 63.7, 55.1, 52.9, 43.8, 8.2, 4.0; HRMS(ESI) m/z [M+H]⁺ calcd. for C₂₇H₃₂N₅O₃S, 506.2226; found 506.2209.

4-((4-((3-Methoxybenzyl)oxy)-2-(4-(oxetan-3-yl)piperazin-1-yl)pyrimidin-5-yl)thio)benzamide[190r]

A mixture of 189r (10 mg, 0.020 mmol) and KOH (22.4 mg, 0.4 mmol) int-BuOH (2 mL) was heated at 80° C. for 1 h. Solvent was removed underreduced pressure and the residue was purified by preparatory TLC(CH₂Cl₂:MeOH—NH₃ (7 N), 20:1) to afford 4.5 mg (44%) of 190r. ¹H NMR(600 MHz, MeOH-d₄): δ 8.25 (s, 1H), 7.72 (d, J=3.3 Hz, 2H), 7.14 (t,J=7.9 Hz, 1H), 7.10 (d, J=8.5 Hz, 2H), 6.78 (dd, J=8.1, 2.4 Hz, 1H),6.72 (d, J=8.1 Hz, 1H), 6.68 (s, 1H), 5.32 (s, 2H), 4.71 (t, J=6.7 Hz,2H), 4.64 (t, J=6.2 Hz, 2H), 3.90 (m, 4H) 3.64 (s, 3H), 3.51-3.55 (m,1H), 2.42 (m, 4H); ¹³C NMR (150 MHz, MeOH-d₄): δ 171.7, 170.1, 165.9,162.9, 161.1, 144.6, 139.4, 131.7, 130.4, 129.2, 126.8, 120.6, 114.3,113.9, 99.8, 76.5, 68.9, 60.3, 55.6, 50.4, 44.6; HRMS (ESI) m/z [M+H]⁺calcd. for C₂₆H₃₀N₅O₄S, 508.2019; found 508.2014.

4-((4-((3-Methoxybenzyl)oxy)-2-(3,3,4-trimethylpiperazin-1-yl)pyrimidin-5-yl)thio)benzamide [190s]

A mixture of 189s (7.4 mg, 0.015 mmol) and KOH (16.8 mg, 0.3 mmol) int-BuOH (1.5 mL) was heated at 80° C. for 1h. Solvent was removed underreduced pressure and the residue was purified by preparatory TLC(CH₂Cl₂:MeOH—NH₃ (7 N), 15:1) to afford 6.9 mg (93%) of 190s. MS (m/z):[M+H]⁺ 494.1.

4-((4-((3-Methoxybenzyl)oxy)-2-(4-methyl-3-oxopiperazin-1-yl)pyrimidin-5-yl)thio)benzamide [190t]

A mixture of 189t (10 mg, 0.021 mmol) and KOH (24.2 mg, 0.433 mmol) int-BuOH (2 mL) was heated at 80° C. for 45 minutes. Solvent was removedunder reduced pressure and the residue was purified by preparatory TLC(CH₂Cl₂:MeOH—NH₃ (7 N), 20:1) to afford 3.0 mg (30%) of 190t. ¹H NMR(600 MHz, MeOH-d₄): δ 8.30 (s, 1H), 7.72 (d, J=8.6 Hz, 2H), 7.14 (t,J=7.9 Hz, 1H), 7.11 (d, J=8.6 Hz, 2H), 6.78 (dd, J=8.2, 2.3 Hz, 1H),6.72 (d, J=7.6 Hz, 1H), 6.69 (s, 1H), 5.36 (s, 2H), 4.40 (s, 2H), 4.10(t, J=5.4 Hz, 2H), 3.65 (s, 3H), 3.47 (t, J=5.4 Hz, 2H), 3.01 (s, 3H);¹³C NMR (150 MHz, MeOH-d₄): δ 171.6, 170.2, 168.4, 165.9, 162.2, 161.2,144.3, 139.3, 131.8, 130.4, 129.3, 126.9, 120.6, 114.5, 113.8, 100.9,69.1, 55.6, 41.7, 34.7; HRMS (ESI) m/z [M+H]⁺ calcd. for C₂₄H₂₆N₅O₄S,480.1706; found 480.1702.

4-((2-(4-(Furan-2-ylmethyl)piperazin-1-yl)-4-((3-methoxybenzyl)oxy)pyrimidin-5-yl)thio)benzamide[190u]

A mixture of 189u (10 mg, 0.0194 mmol) and KOH (22 mg, 0.39 mmol) int-BuOH (2 mL) was heated at 80° C. for 1 h. Solvent was removed underreduced pressure and the residue was purified by preparatory TLC(CH₂Cl₂:MeOH—NH₃ (7 N), 20:1) to afford 8.8 mg (85%) of 190u. ¹H NMR(600 MHz, CDCl₃): δ 8.26 (s, 1H), 7.62 (d, J=8.5 Hz, 2H), 7.41 (m, 1H),7.16 (t, J=7.9 Hz, 1H), 7.10 (d, J=8.5 Hz, 2H), 6.78 (dd, J=8.2, 2.3 Hz,1H), 6.74 (d, J=7.6 Hz, 1H), 6.66 (s, 1H), 6.34 (m, 1H), 6.24 (d, J=3.0Hz, 1H), 6.03 (br s, 1H), 5.60 (br s, 1H), 5.44 (s, 2H), 3.90 (m, 4H),3.66 (s, 3H), 3.61 (s, 2H), 2.54 (m, 4H); ¹³C NMR (150 MHz, CDCl₃): δ168.7, 168.5, 164.9, 161.5, 159.5, 143.5, 142.4, 137.8, 129.8, 129.3,127.7, 125.8, 119.7, 113.2, 113.1, 110.1, 109.1, 97.7, 67.6, 55.1, 54.8,52.8, 43.7; HRMS (ESI) m/z [M+H]⁺ calcd. for C₂₈H₃₀N₅O₄S, 532.2019;found 532.2020.

4-((4-((3-Methoxybenzyl)oxy)-2-(4-(thiazol-2-ylmethyl)piperazin-1-yl)pyrimidin-5-yl)thio)benzamide[190v]

A mixture of 189u (12 mg, 0.023 mmol) and KOH (25.2 mg, 0.45 mmol) int-BuOH (2 mL) was heated at 80° C. for 1 h. Solvent was removed underreduced pressure and the residue was purified by preparatory TLC(CH₂Cl₂:MeOH—NH₃ (7 N), 20:1) to afford 9.6 mg (76%) of 190v. ¹H NMR(600 MHz, CDCl₃): δ 8.26 (s, 1H), 7.74 (d, J=3.3 Hz, 1H), 7.62 (d, J=8.5Hz, 2H), 7.33 (d, J=3.3 Hz, 1H), 7.16 (t, J=7.9 Hz, 1H), 7.11 (d, J=8.5Hz, 2H), 6.78 (dd, J=8.2, 2.3 Hz, 1H), 6.74 (d, J=7.6 Hz, 1H), 6.68 (s,1H), 6.05 (br s, 1H), 5.51 (br s, 1H), 5.44 (s, 2H), 4.05 (s, 2H), 3.90(m, 4H), 3.66 (s, 3H), 2.66 (m, 4H); ¹³C NMR (150 MHz, CDCl₃): δ 169.4,168.7, 168.5, 164.9, 161.5, 159.5, 143.5, 142.5, 137.8, 129.9, 129.3,127.7, 125.8, 119.7, 113.2, 113.1, 97.8, 67.6, 59.5, 55.1, 52.8, 43.9;HRMS (ESI) m/z [M+H]⁺ calcd. for C₂₇H₂₉N₆O₃S₂, 549.1743; found 549.1761.

Example 25

(R)-4-((4-((3-methoxybenzyl)oxy)-2-(2-methylpiperazin-1-yl)pyrimidin-5-yl)thio)benzonitrile[191]

To 188 (15 mg, 0.039 mmol) in DMF (3 mL) was added(S)-1-N-Boc-2-methylpiperazine (9.4 mg, 0.047 mmol) and Et₃N (10 μL,0.072 mmol) and heated at 90° C. for 2 h. Solvent was removed underreduced pressure and the residue was purified by preparatory TLC(CH₂Cl₂:MeOH, 10:1) to afford Boc-protected intermediate in quantitativeyield. To this was added 1 mL of a solution of CH₂Cl₂:TFA (7:3) andstirred at rt for 4 h. Solvent was removed under reduced pressure andthe residue was purified by preparatory TLC (CH₂Cl₂:MeOH—NH₃ (7 N),20:1) to afford 17 mg (98%) of 191. ¹H NMR (500 MHz, CDCl₃): δ 8.17 (s,1H), 7.35 (d, J=8.4 Hz, 2H), 7.10 (t, J=7.8 Hz, 1H), 7.04 (d, J=8.4 Hz,2H), 6.72 (dd, J=8.1, 1.7, 1H), 6.67 (d, J=7.5 Hz, 1H), 6.60 (s, 1H),5.29 (d, J=12.7 Hz, 1H), 5.24 (d, J=12.7 Hz, 1H), 4.76 (m, 1H),4.42-4.47 (m, 1H), 3.65 (s, 3H), 3.00-3.12 (m, 2H), 2.84-2.94 (m, 2H),2.67-2.73 (m, 1H), 1.22 (d, J=6.8 Hz, 3H); MS (ESI) m/z [M+H]⁺ 448.3.

(R)-4-((2-(2,4-dimethylpiperazin-1-yl)-4-((3-methoxybenzyl)oxy)pyrimidin-5-yl)thio)benzonitrile[192]

To a solution of 191 (17 mg, 0.038 mmol) in MeOH (5 mL) was addedformalin (20 μL, 0.269 mmol), sodium acetate (20 mg, 0.244 mmol) andsodium cyanoborohydride (20 mg, 0.095 mmol) and was heated at 50° C. for5 h. Solvent was removed under reduced pressure and the residue waspurified by preparative TLC (CH₂Cl₂:MeOH, 10:1) to afford 15 mg (86%) of192. MS (ESI) m/z [M+H]⁺ 462.2.

(R)-4-((2-(2,4-dimethylpiperazin-1-yl)-4-((3-methoxybenzyl)oxy)pyrimidin-5-yl)thio)benzamide[193]

A mixture of 192 (15 mg, 0.0325 mmol) and KOH (40 mg, 0.71 mmol) int-BuOH (3 mL) was heated at 80° C. for 1 h. Solvent was removed underreduced pressure and the residue was purified by preparatory TLC(CH₂Cl₂:MeOH—NH₃ (7 N), 20:1) to afford 12.2 mg (78%) of 193. ¹H NMR(500 MHz, CDCl₃) δ 8.28 (s, 1H), 7.62 (d, J=8.2 Hz, 2H), 7.12-7.18 (m,3H), 6.75-6.79 (m, 2H), 6.69 (s, 1H), 6.07 (br s, 1H), 5.81 (br s, 1H),5.35 (d, J=12.0 Hz, 1H), 5.29 (d, J=12.0 Hz, 1H), 4.87 (s, 1H), 4.53 (d,J=13.0 Hz, 1H), 3.69 (s, 3H), 3.28 (t, J=12.6 Hz, 1H), 2.90 (d, J=10.6Hz, 1H), 2.76 (d, J=11.2 Hz, 1H), 2.32 (s, 3H), 2.23 (d, J=10.6 Hz, 1H),2.03 (t, J=11.5 Hz, 1H), 1.31 (d, J=6.6 Hz, 3H); ¹³C NMR (125 MHz,CDCl₃) δ 169.1, 168.8, 165.2, 161.5, 159.8, 143.8, 138.2, 130.1, 129.5,128.0, 126.1, 119.9, 113.4, 113.2, 97.8, 67.8, 60.1, 55.4, 55.3, 47.1,46.7, 39.3, 15.6; HRMS (ESI) m/z [M+H]⁺ calcd. for C₂₅H₃₀N₅O₃S 480.2069;found 480.2054.

Example 26

4-((4-((3-Methoxybenzyl)oxy)-2-(5-methyl-2,5-diazabicyclo[2.2.11]heptan-2-yl)pyrimidin-5-yl)thio)benzonitrile[194]

To 188 (15.0 mg, 0.039 mmol) in DMF (2 mL) was added a tert-butyl2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (11.6 mg, 0.0585 mmol) andheated at 90° C. for 2 h. Solvent was removed under reduced pressure andto the residue was added CH₂Cl₂ (3 mL) followed by TFA (1 mL) dropwiseover 5 minutes and the reaction mixture was stirred at rt for 2 h. Thereaction mixture was concentrated under reduced pressure and dried underhigh vacuum overnight. This residue was taken up into CH₃OH (3 mL) andto this was added 37% formaldehyde (40 μL, 15 mg, 0.495 mmol), sodiumtriacetoxyborohydride (35 mg, 0.165 mmol) and sodium acetate (27 mg,0.330 mmol) and the reaction was heated at 50° C. for 5 h. Solvent wasremoved under reduced pressure and the residue was purified bypreparatory TLC (CH₂Cl₂:MeOH, 10:1) to afford 16.2 mg (91%) of 194. MS(m/z): [M+H]⁺ 460.18.

4-((4-((2-Aminopyridin-4-yl)methoxy)-2-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyrimidin-5-yl)thio)benzamide [195]

A mixture of 194 (16.2 mg, 0.0353 mmol) and KOH (39.5 mg, 0.706 mmol) int-BuOH (3 mL) was heated at 80° C. for 1 h. Solvent was removed underreduced pressure and the residue was purified by preparatory TLC(CH₂Cl₂:MeOH—NH₃ (7 N), 20:1) to afford 10.0 mg (60%) of 195. ¹H NMR(600 MHz, CDCl₃): δ 8.19 (s, 1H), 7.55 (d, J=8.2 Hz, 2H), 7.09 (t, J=7.9Hz, 1H), 7.03 (d, J=8.2 Hz, 2H), 6.68-6.72 (m, 2H), 6.61 (s, 1H), 5.99(br s, 1H), 5.62 (br s, 1H), 5.52 (s, 2H), 4.73-4.78 (m, 1H), 3.35-3.74(m, 3H), 3.61 (s, 3H), 2.96 (m, 1H), 2.50-2.70 (m, 1H), 2.41 (s, 3H),1.78-1.99 (m, 2H); HRMS (ESI) m/z [M+H]⁺ calcd. for C₂₅H₂₈N₅O₃S,478.1913; found 478.1897.

Example 27

4-((4-((3-Methoxybenzyl)oxy)-2-(piperazin-1-yl)pyrimidin-5-yl)thio)benzonitrile[196]

To 188 (75 mg, 0.195 mmol) was added piperazine (47 mg, 0.254 mmol) andEt₃N (50 μL, 0.36 mmol) in DMF (4 mL) and heated at 90° C. for 2 h.Solvent was removed under reduced pressure and the residue was purifiedby preparatory TLC (CH₂Cl₂:MeOH, 10:1) to afford Boc-protectedintermediate in quantitative yield. To this was added 5 mL of a solutionof CH₂Cl₂:TFA (7:3) and stirred at rt for 2 h. Solvent was removed underreduced pressure and the residue was purified by preparatory TLC(CH₂Cl₂:MeOH—NH₃ (7 N), 20:1) to afford 58 mg (69%) of 196. MS (ESI) m/z[M+H]⁺ 434.3.

4-((4-((3-Methoxybenzyl)oxy)-2-(4-(prop-2-yn-1-yl)piperazin-1-yl)pyrimidin-5-yl)thio)benzonitrile[197]

A mixture of 196 (20 mg, 0.046 mmol), propargyl bromide (80% in toluene;8.2 mg, 0.055 mol,) and Et₃N (14 mg, 0.138 mmol) in DMF (1 mL) washeated at 90° C. for 1h. Solvent was removed under reduced pressure andthe residue was purified by preparatory TLC (CH₂Cl₂:MeOH—NH₃ (7 N),30:1) to afford 14 mg (63%) of 197. MS (ESI) m/z [M+H]⁺ 472.3.

4-((4-((3-Methoxybenzyl)oxy)-2-(4-(prop-2-yn-1-yl)piperazin-1-yl)pyrimidin-5-yl)thio)benzamide[198]

A mixture of 197 (10 mg, 0.021 mmol) and KOH (26 mg, 0.466 mmol) int-BuOH (3 mL) was heated at 80° C. for 1 h. Solvent was removed underreduced pressure and the residue was purified by preparatory TLC(CH₂Cl₂:MeOH—NH₃ (7 N), 20:1) to afford 3.6 mg (35%) of 198. ¹H NMR (500MHz, CDCl₃) δ 8.29 (s, 1H), 7.63 (d, J=8.5 Hz, 2H), 7.18 (t, J=7.9 Hz,1H), 7.12 (d, J=8.5 Hz, 2H), 6.79 (dd, J=8.2, 2.3 Hz, 1H), 6.75 (d,J=7.6 Hz, 1H), 6.68 (s, 1H), 6.04 (br s, 1H), 5.60 (br s, 1H), 5.34 (s,2H), 4.06 (m, 4H), 3.70 (s, 3H), 3.57 (s, 2H), 2.85 (m, 4H), 2.42 (s,1H); HRMS (ESI) m/z [M+H]⁺ calcd. for C₂₆H₂₈N₅O₃S 490.1913; found490.1899.

Example 28

(R)-1-(4-((4-Methoxybenzyl)oxy)pyrimidin-2-yl)-N,N-dimethylpyrrolidin-3-amine[200]

To a solution of 2-chloro-4-((4-methoxybenzyl)oxy)pyrimidine (199; 0.9g, 3.60 mmol) in DMF (10 mL) was added(R)—N,N-dimethylpyrrolidin-3-amine (0.67 mL, 0.62 g, 5.4 mmol) andheated at 90° C. for 2 h. Solvent was removed under reduced pressure andthe crude product was purified by column chromatography (CH₂Cl₂:MeOH—NH₃(7 N), 50:1) to give 1.12 g (86%) of an oil 200. ¹H NMR (500 MHz,CDCl₃): δ 8.05 (d, J=5.7 Hz, 1H), 7.37 (d, J=8.5 Hz, 2H), 6.89 (d, J=8.5Hz, 2H), 5.99 (d, J=5.7, 2H), 5.31 (s, 2H), 3.91-3.96 (m, 1H), 3.83-3.88(m, 1H), 3.81 (s, 3H), 3.46-3.53 (m, 1H), 3.28-3.32 (m, 1H), 2.73-2.81(m, 1H), 2.33 (s, 6H), 2.18-2.24 (m, 1H), 1.84-1.95 (m, 1H); ¹³C NMR(125 MHz, CDCl₃): δ 169.4, 160.3, 159.6, 158.2, 130.1, 129.2, 114.0,96.4, 67.2, 65.7, 55.5, 51.1, 45.9, 44.6, 30.6; MS (ESI) m/z [M+H]⁺329.2.

(R)-1-(5-Iodo-4-((4-methoxybenzyl)oxy)pyrimidin-2-yl)-N,N-dimethylpyrrolidin-3-amine[201]

To 200 (1.12 g, 3.41 mmol) in acetonitrile (17 mL) was addedN-iodosuccinimide (0.917 g, 4.09 mmol) and TFA (1.02 mL, 1.56 g, 13.65mmol), and the reaction mixture was stirred at rt for 1.5 h. Thereaction mixture was basified with Na₂CO₃ (pH ˜8), concentrated todryness and the residue was taken up into EtOAc (150 mL) and washed with10% sodium thiosulfate (50 mL) and brine (2×40 mL). The organic layerwas dried over MgSO₄, filtered and concentrated to give a residue whichwas purified by column chromatography (CH₂Cl₂:MeOH—NH₃ (7 N), 50:1) toyield 1.13 g (76%) of 201. ¹H NMR (500 MHz, CDCl₃): δ 8.26 (s, 1H), 7.38(d, J=8.6 Hz, 2H), 6.89 (d, J=8.6 Hz, 2H), 5.36 (s, 2H), 3.83-3.89 (m,1H), 3.81 (s, 3H), 3.73-3.79 (m, 1H), 3.43-3.51 (m, 1H), 3.28-3.33 (m,1H), 2.78-2.84 (m, 1H), 2.34 (s, 6H), 2.18-2.24 (m, 1H), 1.86-1.96 (m,1H); MS (ESI) m/z [M+H]⁺ 455.1.

(R)-4-((2-(3-(dimethylamino)pyrrolidin-1-yl)-4-((4-methoxybenzyl)oxy)pyrimidin-5-yl)thio)benzonitrile[202]

A mixture of 201 (0.7 g, 1.54 mmol), 4-mercaptobenzonitrile (0.25 g,1.85 mmol) and K₂CO₃ (0.64 g, 4.62 mmol) in DMF (20 mL) was evacuatedand backfilled with argon three times. Copper(I)thiophene-2-carboxylate(0.12 g, 0.61 mmol) was added and evacuated and backfilled with argontwo times and the reaction mixture was heated at 130° C. for 16 h.Solvent was removed under reduced pressure and purified by columnchromatography (CH₂Cl₂:CH₃OH, 10:1) to give 0.42 g (58%) of 202. MS(ESI) m/z [M+H]⁺ 462.1.

(R)-4-((2-(3-(Dimethylamino)pyrrolidin-1-yl)-4-hydroxypyrimidin-5-yl)thio)benzonitrile[203]

3 mL of CH₂Cl₂ and 4 mL of TFA was added to 202 (0.42 g, 0.9 mmol) andstirred at rt for 2 h. The reaction mixture was concentrated underreduced pressure and the residue was purified by column chromatography(CH₂Cl₂:CH₃OH, 10:1) to give 0.30 g (97%) of 203. MS (m/z): [M+H]⁺342.1.

(R)-4-((4-Chloro-2-(3-(dimethylamino)pyrrolidin-1-yl)pyrimidin-5-yl)thio)benzonitrile[204]

203 (0.12 g, 0.35 mmol) and POCl₃ (2 mL) were heated at 100° C. for 1 h.After cooling to rt, the reaction mixture was added to a beakercontaining ice chips. Following complete quenching of POCl₃, solidNa₂CO₃ was carefully added until pH˜9. This was transferred to aseperatory funnel and extracted with CH₂Cl₂ (4×50 mL), dried over MgSO₄,filtered and concentrated to a solid which was purified by columnchromatography (CH₂Cl₂:MeOH, 40:1 to 20:1) to afford 0.12 g (95%) of204. ¹H NMR (500 MHz, CDCl₃): δ 8.40 (s, 1H), 7.51 (d, J=8.3 Hz, 2H),7.12 (d, J=8.4 Hz, 2H), 3.94-3.99 (m, 1H), 3.83-3.91 (m, 1H), 3.53-3.60(m, 1H), 3.41-3.45 (m, 1H), 2.84-2.91 (m, 1H), 2.37 (s, 6H), 2.24-2.30(m, 1H), 1.96-2.03 (m, 1H); MS (ESI) m/z [M+H]⁺ 360.10.

(R)-4-((2-(3-(Dimethylamino)pyrrolidin-1-yl)-4-((3-(trifluoromethoxy)benzyl)oxy)pyrimidin-5-yl)thio)benzamide[205]

To (3-(trifluoromethoxy)phenyl)methanol (6.3 μL, 8.1 mg, 0.042 mmol)dissolved in CH₃CN (1 mL) was added NaH (2.8 mg, 0.116 mmol) and theresulting suspension was stirred for 10 min. at rt. Then 204 (10 mg,0.0289 mmol) was added and the reaction mixture was stirred at rt for2.5 h. MeOH (1 mL) was added and stirred for 5 minutes then the reactionmixture was concentrated under reduced pressure to give a residue whichwas partially purified by preparatory TLC (CH₂Cl₂:MeOH—NH₃ (7 N), 20:1)to afford 8.2 mg of intermediate nitrile (MS (m/z): [M+H]⁺ 516.2). Amixture of this and KOH (20.0 mg, 0.35 mmol) in t-BuOH (1 mL) was heatedat 80° C. for 1 h. Solvent was removed under reduced pressure and theresidue was purified by preparatory TLC (CH₂Cl₂:MeOH—NH₃ (7 N), 10:1) toafford 6.6 mg (78%) of 205. ¹H NMR (600 MHz, CDCl₃): δ 8.23 (s, 1H),7.64 (d, J=8.5 Hz, 2H), 7.25 (d, J=7.9 Hz, 1H), 7.12 (d, J=8.5 Hz, 2H),7.09 (d, J=8.7, 1H), 7.07 (t, J=7.3, 1H), 7.05 (s, 1H), 6.00 (br s, 1H),5.62 (br s, 1H), 5.37 (s, 2H), 3.93-3.99 (m, 1H), 3.78-3.87 (m, 1H),3.45-3.56 (m, 1H), 3.03-3.40 (m, 1H), 2.77-2.86 (m, 1H), 2.34 (s, 6H),2.20-2.25 (m, 1H), 1.90-1.96 (m, 1H); ¹³C NMR (150 MHz, CDCl₃+CD₃OD): δ168.6, 168.2, 165.1, 160.2, 149.1, 143.7, 138.9, 129.9, 129.7, 127.8,125.7, 125.6, 125.5, 121.9 (q, J=255.6 Hz), 120.2, 119.9, 97.3, 66.7,65.4, 51.1, 45.9, 44.3, 30.1; HRMS (ESI) m/z [M+H]⁺ calcd. forC₂₅H₂₇F₃N₅O₃S, 534.1787; found 534.1782.

(R)-4-((4-((2-Aminopyridin-4-yl)methoxy)-2-(3-(dimethylamino)pyrrolidin-1-yl)pyrimidin-5-yl)thio)benzamide[206]

To ((2-aminopyridin-4-yl)methanol (5.4 mg, 0.042 mmol) dissolved inCH₃CN (1 mL) was added NaH (2.8 mg, 0.116 mmol) and the resultingsuspension was stirred for 10 min. at rt. Then 204 (10 mg, 0.0289 mmol)was added and the reaction mixture was stirred at rt for 2.5 h. MeOH (1mL) was added and stirred for 5 minutes then the reaction mixture wasconcentrated under reduced pressure to give a residue which was purifiedby preparatory TLC (CH₂Cl₂:MeOH—NH₃ (7 N), 20:1) to afford 8.0 mg ofintermediate nitrile (MS (m/z): [M+H]⁺ 448.2). A mixture of this and KOH(22.0 mg, 0.39 mmol) in t-BuOH (1 mL) was heated at 80° C. for 1 h.Solvent was removed under reduced pressure and the residue was purifiedby preparatory TLC (CH₂Cl₂:MeOH—NH₃ (7 N), 10:1) to afford 4.8 mg (58%)of 206. ¹H NMR (600 MHz, CDCl₃): δ 8.31 (s, 1H), 7.92 (s, 1H), 7.66 (d,J=8.3 Hz, 2H), 7.17 (d, J=8.2 Hz, 2H), 6.43 (m, 1H), 6.10 (br s, 1H),5.93 (m, 1H), 2H), 5.62 (br s, 1H), 5.25 (s, 2H), 4.46 (br s, 2H),3.75-3.98 (m, 2H), 3.42-3.56 (m, 1H), 3.27-3.38 (m, 1H), 2.75-2.82 (m,1H), 2.33 (s, 6H), 2.20-2.25 (m, 1H), 1.86-1.96 (m, 1H); HRMS (ESI) m/z[M+H]⁺ calcd. for C₂₃H₂₈N₇O₂S, 466.2025; found 466.2020.

(R)-4-((4-(Benzyloxy)-2-(3-(dimethylamino)pyrrolidin-1-yl)pyrimidin-5-yl)thio)benzamide[207]

To benzylalcohol (4.34 μL, 4.54 mg, 0.042 mmol) dissolved in CH₃CN (1mL) was added NaH (2.8 mg, 0.116 mmol) and the resulting suspension wasstirred for 10 min. at rt. Then 204 (10 mg, 0.0289 mmol) was added andthe reaction mixture was stirred at rt for 2.5 h. MeOH (1 mL) was addedand stirred for 5 minutes then the reaction mixture was concentratedunder reduced pressure to give a residue which was purified bypreparatory TLC (CH₂Cl₂:MeOH—NH₃ (7 N), 20:1) to afford 8.0 mg ofintermediate nitrile (MS (m/z): [M+H]⁺ 432.2). A mixture of this and KOH(22.0 mg, 0.39 mmol) in t-BuOH (1 mL) was heated at 80° C. for 1 h.Solvent was removed under reduced pressure and the residue was purifiedby preparatory TLC (CH₂Cl₂:MeOH—NH₃ (7 N), 20:1) to afford 5.2 mg (63%)of 207. ¹H NMR (600 MHz, CDCl₃): δ 8.27 (s, 1H), 7.62 (d, J=8.5 Hz, 2H),7.22-7.24 (m, 3H0, 7.15 (m, 2H), 7.11 (d, J=8.5 Hz, 2H), 5.99 (br s,1H), 5.62 (br s, 1H), 5.39 (s, 2H), 3.81-3.98 (m, 2H), 3.48-3.55 (m,1H), 3.31-3.37 (m, 1H), 2.76-2.83 (m, 1H), 2.34 (s, 6H), 2.19-2.25 (m,1H), 1.88-1.96 (m, 1H); HRMS (ESI) m/z [M+H]⁺ calcd. for C₂₄H₂₈N₅O₂S,450.1964; found 450.1962.

(R)-4-((2-(3-(Dimethylamino)pyrrolidin-1-yl)-4-((4-fluoro-3-methoxybenzyl)oxy)pyrimidin-5-yl)thio)benzamide[208]

To (4-fluoro-3-methoxyphenyl)methanol (5.52 μL, 6.6 mg, 0.042 mmol)dissolved in CH₃CN (1 mL) was added NaH (2.8 mg, 0.116 mmol) and theresulting suspension was stirred for 10 min. at rt. Then 204 (10 mg,0.0289 mmol) was added and the reaction mixture was stirred at rt for2.5 h. MeOH (1 mL) was added and stirred for 5 minutes then the reactionmixture was concentrated under reduced pressure to give a residue whichwas purified by preparatory TLC (CH₂Cl₂:MeOH—NH₃ (7 N), 20:1) to afford7.2 mg of intermediate nitrile (MS (m/z): [M+H]⁺ 480.2). A mixture ofthis and KOH (18.5 mg, 0.33 mmol) in t-BuOH (1 mL) was heated at 80° C.for 1 h. Solvent was removed under reduced pressure and the residue waspurified by preparatory TLC (CH₂Cl₂:MeOH—NH₃ (7 N), 20:1) to afford 4.1mg (55%) of 208. ¹H NMR (600 MHz, CDCl₃): δ 8.28 (s, 1H), 7.60 (d, J=8.5Hz, 2H), 7.06 (d, J=8.5 Hz, 2H), 6.93-6.97 (m, 1H), 6.74-6.79 (m, 2H),6.01 (br s, 1H), 5.55 (br s, 1H), 5.34 (s, 2H), 3.83-3.99 (m, 2H),3.52-3.57 (m, 1H), 3.35-3.40 (m, 1H), 2.79-2.85 (m, 1H), 2.35 (s, 6H),2.20-2.27 (m, 1H), 1.92-2.05 (m, 1H); ¹³C NMR (150 MHz, CDCl₃): δ 168.5,165.1, 160.3, 152.8, 151.2, 147.5, 143.9, 132.8, 129.7, 127.7, 125.4,120.6, 115.6, 113.0, 97.1, 67.3, 65.3, 56.1, 51.1, 45.9, 44.3, 30.1;HRMS (ESI) m/z [M+H]⁺ calcd. for C₂₅H₂₉FN₅O₃S, 498.1975; found 498.1980.

Example 29

2-Chloro-4-((2,4-dihydroxypyrimidin-5-yl)thio)benzonitrile [209]

A mixture of 5-iodopyrimidine-2,4-diol (174; 2.7 g, 0.011 mmol),2-chloro-4-mercaptobenzonitrile (2.5 g, 0.015 mmol) and K₂CO₃ (4.71 g,0.034 mmol) in DMF (80 mL) was evacuated and backfilled with argon threetimes. Copper(I)thiophene-2-carboxylate (0.865 g, 0.0046 mmol) was addedand evacuated and backfilled with argon two times and the reactionmixture was heated at 130° C. for 16 h. Solvent was removed underreduced pressure and purified by column chromatography(CH₂Cl₂:CH₃OH:CH₃COOH, 15:1:0.1) to give 2.0 g (65%) of 209. MS (ESI)m/z 278.0 [M−H]⁻.

2-Chloro-4-((2,4-dichloropyrimidin-5-yl)thio)benzonitrile [210].A

To a mixture of 209 (2.0 g, 7.14 mmol) and POCl₃ (25 mL) was added DIEA(3.11 mL, 2.31 g, 17.9 mmol) and the reaction was heated at 100° C. for4 h. After cooling to rt, the reaction mixture was added to a beakercontaining ice chips. Following complete quenching of POCl₃, solidNa₂CO₃ was carefully added until pH˜9. This was transferred to aseperatory funnel and extracted with CH₂Cl₂ (4×100 mL), dried overMgSO₄, filtered and concentrated to a solid which was purified by columnchromatography (hexane:EtOAc, 80:20) to afford 0.935 g (41%) of 210.

2-Chloro-4-((2-chloro-4-((4-fluoro-3-methoxybenzyl)oxy)pyrimidin-5-yl)thio)benzonitrile[211]

To (4-fluoro-3-methoxyphenyl)methanol (75.9 μL, 90.7 mg, 0.5809 mmol)dissolved in CH₃CN (5 mL) was added NaH (17.0 mg, 0.6971 mmol) and theresulting suspension was stirred for 10 min. at rt. Then 210 (183 mg,0.5809 mmol) was added and the reaction mixture was stirred at rt for2.5 h. MeOH (1 mL) was added and stirred for 5 minutes then the reactionmixture was concentrated under reduced pressure to give a residue whichwas purified by preparatory TLC (n-hexane:EtOAc, 8:2) to afford 59.2 mgof 211. ¹H NMR (500 MHz, CDCl₃): δ 8.42 (s, 1H), 7.41 (d, J=8.2 Hz, 1H),7.09 (s, 1H), 6.92-6.98 (m, 2H), 6.86 (d, J=8.0 Hz, 1H), 6.66-6.84 (m,1H), 5.32 (s, 2H), 3.79 (s, 3H); ¹³C NMR (125 MHz, CDCl₃): δ 168.7,163.7, 161.5, 153.7, 151.7, 147.7, 142.8, 134.1, 130.6, 128.4, 126.1,121.5, 116.4, 115.7, 114.3, 112.1, 111.1, 70.0, 56.4; MS (ESI) m/z[M+H]⁺ 436.0.

(R)-2-Chloro-4-((2-(3-(dimethylamino)pyrrolidin-1-yl)-4-((4-fluoro-3-methoxybenzyl)oxy)pyrimidin-5-yl)thio)benzamide[212]

To 211 (10.0 mg, 0.023 mmol) was added a(R)—N,N-dimethylpyrrolidin-3-amine (11 μL, 10.5 mg, 0.0919 mmol) in DMF(2 mL) and heated at 90° C. for 2 h. Solvent was removed under reducedpressure to give a residue which was purified by preparatory TLC(CH₂Cl₂:MeOH—NH₃ (7 N), 20:1) to afford 8.7 mg (74%) of intermediatenitrile (MS (m/z): [M+H]⁺ 514.1). A mixture of this and KOH (18.0 mg,0.318 mmol) in t-BuOH (2 mL) was heated at 80° C. for 1 h. Solvent wasremoved under reduced pressure and the residue was purified bypreparatory TLC (CH₂Cl₂:MeOH—NH₃ (7 N), 20:1) to afford 7.2 mg (80%) of212. ¹H NMR (600 MHz, CD₂Cl₂): δ 8.16 (s, 1H), 7.48 (d, J=8.1 Hz, 1H),6.90-6.94 (m, 2H), 6.88 (d, J=8.2 Hz, 1H), 6.76 (dd, J=8.2, 1.6 Hz, 1H),6.71 (s, 1H), 6.27 (br s, 1H), 5.81 (br s, 1H), 5.27 (s, 2H), 3.73-3.88(m, 2H), 3.63 (s, 3H), 3.42-3.46 (m, 1H), 3.26-3.33 (m, 1H), 2.76-2.80(m, 1H), 2.26 (s, 3H), 2.25 (s, 3H), 2.12-2.15 (m, 1H), 1.86-2.90 (m,1H); ¹³C NMR (150 MHz, CD₂Cl₂): δ 168.8, 165.6, 160.9, 153.2, 151.2,147.8, 144.5, 133.4, 131.7, 131.1, 130.6, 126.9, 124.5, 120.6, 116.1,113.4, 96.5, 67.7, 65.6, 56.5, 51.3, 46.4, 44.3, 30.2; HRMS (ESI) m/z[M+H]⁺ calcd. for C₂₅H₂₈ClFN₅O₃S, 532.1585; found 532.1592.

(R)-4-((2-(3-Aminopyrrolidin-1-yl)-4-((4-fluoro-3-methoxybenzyl)oxy)pyrimidin-5-yl)thio)-2-chlorobenzamide[213]

To 211 (30.0 mg, 0.069 mmol) was added a(R)—N,N-dimethylpyrrolidin-3-amine (18.1 μL, 17.8 mg, 0.206 mmol) in DMF(2 mL) and heated at 90° C. for 2 h. Solvent was removed under reducedpressure to give a residue which was purified by preparatory TLC(CH₂Cl₂:MeOH—NH₃ (7 N), 15:1) to afford 28.0 mg (84%) of intermediatenitrile (MS (m/z): [M+H]⁺ 486.1). A mixture of this and KOH (64.6 mg,1.154 mmol) in t-BuOH (5 mL) was heated at 80° C. for 1 h. Solvent wasremoved under reduced pressure and the residue was purified bypreparatory TLC (CH₂Cl₂:MeOH—NH₃ (7 N), 10:1) to afford 25.7 mg (86%) of213. ¹H NMR (600 MHz, CDCl₃/MeOH-d₄): δ 8.15 (s, 1H), 7.45 (d, J=8.1 Hz,1H), 6.84-6.92 (m, 3H), 6.67-6.76 (m, 2H), 5.27 (s, 2H), 3.73-3.80 (m,2H), 3.67 (s, 3H), 3.58-3.62 (m, 1H), 3.27-3.34 (m, 2H), 2.10-2.14 (m,1H), 1.78-1.82 (m, 1H); ¹³C NMR (150 MHz, CDCl₃/MeOH-d₄): δ 168.5,164.7, 160.3, 152.8, 151.2, 147.4, 143.7, 132.5, 131.4, 130.4, 130.2,126.6, 124.1, 120.2, 115.7, 112.9, 96.7, 67.4, 56.1, 54.5, 50.5, 45.1,33.2; HRMS (ESI) m/z [M+H]⁺ calcd. for C₂₃H₂₄ClFN₅O₃S, 504.1272; found504.1275.

(R)-2-Chloro-4-((4-((4-fluoro-3-methoxybenzyl)oxy)-2-(3-(methylamino)pyrrolidin-1-yl)pyrimidin-5-yl)thio)benzamide[214]

To 211 (12.0 mg, 0.0276 mmol) was added a (R)—N-methylpyrrolidin-3-amine(9.7 μL, 9.1 mg, 0.206 mmol) in DMF (2 mL) and heated at 90° C. for 2 h.Solvent was removed under reduced pressure to give a residue which waspurified by preparatory TLC (CH₂Cl₂:MeOH—NH₃ (7 N), 20:1) to afford 11.6mg (84%) of intermediate nitrile (MS (m/z): [M+H]⁺ 500.1). A mixture ofthis and KOH (26.0 mg, 0.465 mmol) in t-BuOH (2 mL) was heated at 80° C.for 1 h. Solvent was removed under reduced pressure and the residue waspurified by preparatory TLC (CH₂Cl₂:MeOH—NH₃ (7 N), 15:1) to afford 7.6mg (64%) of 214. ¹H NMR (500 MHz, CD₂Cl₂/MeOH-d₄): δ 8.15 (s, 1H), 7.45(d, J=8.1 Hz, 1H), 6.90-6.94 (m, 2H), 6.77 (dd, J=1.9 and 8.1 Hz, 1H),6.68-6.72 (m, 1H), 5.27 (s, 2H), 3.63-3.76 (m, 2H), 3.65 (s, 3H),3.55-3.56 (m, 1H), 3.25-3.41 (m, 2H), 2.41 (s, 3H), 2.12-2.19 (m, 1H),1.82-1.86 (m, 1H); HRMS (ESI) m/z [M+H]⁺ calcd. for C₂₄H₂₆ClFN₅O₃S,518.1278; found 518.1280.

Example 30

4-((2,4-Dihydroxypyrimidin-5-yl)thio)-2-(trifluoromethyl)benzonitrile[215]

A mixture of 5-iodopyrimidine-2,4-diol 174 (3.77 g, 15.8 mmol),4-mercapto-2-(trifluoromethyl)benzonitrile (3.86 g, 19.0 mmol) and K₂CO₃(6.55 g, 47.4 mmol) in DMF (100 mL) was evacuated and backfilled withargon three times. Copper(I)thiophene-2-carboxylate (1.21 g, 6.32 mmol)was added and evacuated and backfilled with argon two times and thereaction mixture was heated at 130° C. for 16 h. Solvent was removedunder reduced pressure and purified by column chromatography(CH₂Cl₂:CH₃OH:CH₃COOH, 25:1:0.3) to give 2.54 g (51%) of 215. MS (ESI)m/z 312.0 [M−H]⁻.

4-((2,4-Dichloropyrimidin-5-yl)thio)-2-(trifluoromethyl)benzonitrile[216]

0.320 g (1.022 mmol) of 215 was added 7 mL of POCl₃ (4 g, 25.55 mmol)with stirring. To this mixture 450 μL of DIEA (0.33 g, 2.55 mmol) wasadded slowly and the reaction was heated at 100° C. for 4 h. Aftercooling to rt, the reaction mixture was added to a beaker containing icechips. Following complete quenching of POCl₃, solid Na₂CO₃ was carefullyadded until pH˜9. This was transferred to a seperatory funnel andextracted with CH₂Cl₂ (4×75 mL), dried over MgSO₄, filtered andconcentrated to a solid which was purified by column chromatography(hexane:EtOAc, 80:20) to afford 0.25 g (70%) of 216. ¹H NMR (600 MHz,CDCl₃): δ 8.64 (s, 1H), 7.83 (d, J=8.2 Hz, 1H), 7.69 (d, J=1.7 Hz, 1H),7.45 (dd, J=1.7, 8.2 Hz, 1H); MS (ESI) m/z 383.8/385.8 [M+Cl]⁻.

4-((2-Chloro-4-((3-chlorobenzyl)oxy)pyrimidin-5-yl)thio)-2-(trifluoromethyl)benzonitrile[217]

To 3-chlorobenzylalcohol (101 mg, 0.71 mmol) dissolved in CH₃CN (2 mL)was added NaH (22 mg, 0.923 mmol) and the resulting suspension wasstirred for 10 min. at rt. Then 216 (0.250 g, 0.71 mmol) was added andthe reaction mixture was stirred at rt for 4 h. The reaction mixture wasconcentrated under reduced pressure to give a residue which was purifiedby preparatory TLC (hexane:CH₂Cl₂, 40:60) to afford 110 mg (34%) of 217.MS (ESI) m/z [M+H]⁺ 456.1.

General Procedure for Synthesis of 218 and 225-229.

To 217 (1 equiv.) was added amine (1.5 equiv.) and Et₃N (2 equiv.) inDMF and heated at 90° C. for 2 h. Solvent was removed under reducedpressure and the residue was purified by prepatory TLC to affordintermediate nitrile. A mixture of the nitrile (1 equiv.) and KOH (25equiv.) in t-BuOH was heated at 80° C. for 1 h. Solvent was removedunder reduced pressure and the residue was purified by preparatory TLCto afford desired amide.

(R)-4-((4-((3-Chlorobenzyl)oxy)-2-(3-(dimethylamino)pyrrolidin-1-yl)pyrimidin-5-yl)thio)-2-(trifluoromethyl)benzamide[218]. 218 was obtained in 51% yield following the general procedureabove. ¹H NMR (600 MHz, CDCl₃) δ 8.28 (s, 1H), 7.41-7.45 (m, 2H),7.16-7.24 (m, 4H), 7.03-7.07 (m, 1H), 5.96 (br s, 1H), 5.83 (br s, 1H),5.29-5.38 (m, 2H), 3.81-4.00 (m, 2H), 3.48-3.56 (m, 1H), 3.35-3.43 (m,1H), 2.88-2.89 (m, 1H), 2.38 (d, J=12.1 Hz, 6H), 2.23-2.27 (m, 1H),1.94-2.03 (m, 1H); HRMS (ESI) m/z [M+H]⁺ calcd. for C₂₅H₂₆ClF₃N₅O₂S552.1448; found 552.1457.

4-((4-((3-Chlorobenzyl)oxy)-2-(3-(dimethylamino)azetidin-1-yl)pyrimidin-5-yl)thio)-2-(trifluoromethyl)benzamide[225]

225 was obtained in 36% yield following the general procedure above. ¹HNMR (600 MHz, CD₂Cl₂) δ 8.25 (s, 1H), 7.44 (d, J=1.5 Hz, 1H), 7.41 (d,J=8.2 Hz, 1H), 7.22-7.26 (m, 2H), 7.18-7.22 (m, 2H), 7.06-7.09 (m, 1H),5.77 (br s, 2H), 5.33 (s, 2H), 4.16-4.19 (m, 2H), 4.03 (m, 2H), 3.28 (brs, 1H), 2.26 (s, 6H); ¹³C NMR (150 MHz, CD₂Cl₂) δ 169.2, 169.1, 165.7,163.2, 142.5, 139.1, 134.4, 132.3, 130.3, 129.6, 129.5, 128.5, 128.4,128.2 (q, J=31.9 Hz), 126.4, 124.4 (q, J=5.1 Hz), 123.9 (q, J=272.3 Hz),98.0, 67.7, 56.4, 54.6, 42.0; HRMS (ESI) m/z [M+H]⁺ calcd. forC₂₄H₂₄ClF₃N₅O₂S 538.1291; found 538.1306.

4-((4-((3-Chlorobenzyl)oxy)-2-(4-(hex-5-yn-1-yl)piperazin-1-yl)pyrimidin-5-yl)thio)-2-(trifluoromethyl)benzamide[226]

226 was obtained in 48% yield following the general procedure above. ¹HNMR (600 MHz, CDCl₃) δ 8.27 (s, 1H), 7.42-7.46 (m, 2H), 7.18-7.26 (m,3H), 7.14 (s, 1H), 7.01-7.06 (m, 1H), 5.93 (br s, 1H), 5.82 (br s, 1H),5.32 (s, 2H), 3.88 (m, 4H), 2.52 (m, 4H), 2.40-2.45 (m, 2H), 2.25 (td,J=7.0, 2.6 Hz, 2H), 1.98 (t, J=2.6 Hz, 1H), 1.64-1.70 (m, 2H), 1.56-1.62(m, 2H); ¹³C NMR (150 MHz, CDCl₃) δ 169.4, 168.5, 165.3, 161.7, 142.2,138.5, 134.3, 131.6, 130.0, 129.3, 129.1, 128.3, 128.0 (q, J=29.7 Hz),127.7, 125.6, 124.0 (q, J=5.2 Hz), 123.4 (q, J=271.3 Hz), 96.9, 84.4,68.8, 67.2, 58.2, 53.0, 44.1, 26.5, 25.9, 18.5; HRMS (ESI) m/z [M+H]⁺calcd. for C₂₉H₃₀ClF₃N₅O₂S 604.1761; found 604.1786.

4-((4-((3-Chlorobenzyl)oxy)-2-(4-cyclopropylpiperazin-1-yl)pyrimidin-5-yl)thio)-2-(trifluoromethyl)benzamide[227]

227 was obtained in 69% yield following the general procedure above. ¹HNMR (600 MHz, CDCl₃) δ 8.27 (s, 1H), 7.45 (m, 1H), 7.43 (d, J=8.2 Hz,1H), 7.20-7.24 (m, 3H), 7.15 (s, 1H), 7.04 (m, 1H), 5.79-5.81 (d, J=8.4Hz, 2H), 5.32 (s, 2H), 3.82 (m, 4H), 2.67 (m, 4H), 1.65 (m, 1H),0.48-0.52 (m, 4H); ¹³C NMR (150 MHz, CDCl₃) δ 169.1, 168.3, 165.1,161.6, 142.1, 138.3, 134.1, 131.4, 129.8, 129.2, 129.0, 128.1, 127.8 (q,J=31.9 Hz), 127.5, 125.4, 123.8 (q, J=5.3 Hz), 123.2 (q, J=272.3 Hz),96.7, 67.0, 53.0, 44.0, 31.0, 5.9; HRMS (ESI) m/z [M+H]⁺ calcd. forC₂₆H₂₆ClF₃N₅O₂S 564.1448; found 564.1456.

4-((4-((3-Chlorobenzyl)oxy)-2-(4-(furan-2-ylmethyl)piperazin-1-yl)pyrimidin-5-yl)thio)-2-(trifluoromethyl)benzamide[228]

228 was obtained in 47% yield following the general procedure above. ¹HNMR (600 MHz, CDCl₃) δ 8.26 (s, 1H), 7.41-7.44 (m, 3H), 7.19-7.26 (m,3H), 7.13 (s, 1H), 7.02-7.03 (m, 1H), 6.34 (m, 1H), 6.24 (d, J=3.0 Hz,1H), 5.78 (br s, 2H), 5.30 (s, 2H), 3.89 (m, 4H), 3.60 (s, 2H),2.53-2.55 (m, 4H); ¹³C NMR (150 MHz, CDCl₃) δ 169.1, 168.3, 165.1,161.6, 151.0, 142.5, 142.1, 138.3, 134.1, 131.4, 129.8, 129.2, 129.0,128.1, 127.8 (q, J=32.0 Hz), 127.5, 125.4, 123.8 (q, J=5.3 Hz), 123.2(q, J=272.6 Hz), 110.1, 109.2, 96.8, 67.0, 54.9, 52.4, 43.8; HRMS (ESI)m/z [M+H]⁺ calcd. for C₂₈H₂₆ClF₃N₅O₃S 604.1397; found 604.1404.

4-((4-((3-Chlorobenzyl)oxy)-2-(4-(thiazol-2-ylmethyl)piperazin-1-yl)pyrimidin-5-yl)thio)-2-(trifluoromethyl)benzamide[229]. 229 was obtained in 48% yield following the general procedureabove. ¹H NMR (600 MHz, CDCl₃) δ 8.27 (s, 1H), 7.74 (d, J=3.1 Hz, 1H),7.43-7.44 (m, 2H), 7.35 (d, J=3.1 Hz, 1H), 7.20-7.24 (m, 3H), 7.13 (s,1H), 7.02-7.03 (m, 1H), 5.78-5.80 (d, J=12.8 Hz, 2H), 5.30 (s, 2H), 3.94(s, 2H), 3.91 (m, 4H), 2.65-2.67 (m, 4H); ¹³C NMR (150 MHz, CDCl₃) δ169.4, 169.0, 168.3, 165.1, 161.6, 142.5, 142.0, 138.3, 134.1, 131.5,129.8, 129.2, 129.1, 128.1, 127.8 (q, J=32.0 Hz), 127.4, 125.4, 123.8(q, J=5.0 Hz), 123.2 (q, J=272.6 Hz), 119.7, 97.0, 67.0, 59.5, 52.8,44.0; HRMS (ESI) m/z [M+H]⁺ calcd. for C₂₇H₂₅ClF₃N₆O₂S₂ 621.1121; found621.1139.

Example 31

Ethyl 2-(4-cyanophenoxy)acetate [276]

A mixture of 4-cyanophenol (275; 4.0 g, 33.6 mmol), ethyl bromoacetate(5.05 g, 30.2 mmol) and K₂CO₃ (5.8 g, 42.2 mmol) in acetonitrile (50 mL)was heated to 80° C. for 12 h. The reaction mixture was concentratedunder reduced pressure and purified by column chromatography(hexane:EtOAc, 0-40% EtOAc) to give 4.7 g (75%) of 276. ¹H NMR (500 MHz,CDCl₃): δ 7.63 (d, J=8.8 Hz, 2H), 6.99 (d, J=8.8 Hz, 2H), 4.69 (s, 2H),4.31 (q, J=7.2 Hz, 2H), 1.32 (t, J=7.2 Hz, 3H); ¹³C NMR (125 MHz,CDCl₃): δ 167.9, 161.0, 134.1, 118.9, 115.4, 105.2, 65.2, 61.7, 14.1; MS(m/z): [M+H]⁺ 205.9.

4-((4-Hydroxy-2-mercaptopyrimidin-5-yl)oxy)benzonitrile [277]

A solution of 276 (2.05 g, 10 mmol) and ethyl formate (2.70 g, 45 mmol)in THF (50 mL) was added dropwise to a suspension of NaH (0.36 g, 15mmol) in THF (10 mL) at 0° C. over 1h. Afterwords, the ice-bath wasremoved and stirring continued at rt for 20 h. Solvent was removed underreduced pressure and the resulting residue was dissolved in ethanol (10mL) and combined with thiourea (0.91 g, 12 mmol) and the reaction wasrefluxed for 18 h. Then 1 M HCl (aq.) was added and the precipitatedsolid was filtered, washed with water and hexane to give 1.66 g (71%) of277. ¹H NMR (500 MHz, CDCl₃/MeOH-d₄): δ 7.76 (d, J=8.0 Hz, 2H), 7.75 (s,1H), 7.18 (d, J=8.0 Hz, 2H); ¹³C NMR (125 MHz, CDCl₃): δ 174.4, 160.5,157.2, 134.4, 134.2, 132.6, 118.8, 116.4, 104.9; MS (m/z): [M−H]⁻ 244.1.

4-((4-Hydroxy-2-(methylthio)pyrimidin-5-yl)oxy)benzonitrile [278]

To a mixture of 277 (500 mg, 2 mmol) and Et₃N (212 mg, 2.1 mmol) in DMF(5 mL) at 0° C. was added methyl iodide (282 mg, 2 mmol). Afterwords theice-bath was removed and stirring continued overnight at rt. Solvent wasremoved under reduced pressure and purified by column chromatography(CH₂Cl₂:MeOH, 0-10% MeOH) to give 461 mg (89%) of 278. ¹H NMR (500 MHz,CDCl₃/MeOH-d₄): δ 7.72 (s, 1H), 7.50 (d, J=8.8 Hz, 2H), 6.92 (d, J=8.8Hz, 2H), 2.47 (s, 3H); ¹³C NMR (125 MHz, CDCl₃): δ; MS (m/z): [M+H]⁺260.0.

4-((4-Chloro-2-(methylthio)pyrimidin-5-yl)oxy)benzonitrile [279]

278 (0.200 g, 0.77 mmol) and POCl₃ (1 mL) were heated at 75° C. for 1 h.After cooling to rt, the reaction mixture was added to a beakercontaining ice chips. Following complete quenching of POCl₃, solidNa₂CO₃ was carefully added until pH˜9. This was transferred to aseperatory funnel and extracted with CH₂Cl₂ (4×25 mL), dried over MgSO₄,filtered and concentrated to a solid which was purified by columnchromatography (CH₂Cl₂:MeOH, 50:1 to 40:1) to afford 0.173 g (81%) of279. MS (m/z): [M+H]⁺ 277.9/279.9.

4-((4-(Benzyloxy)-2-(methylthio)pyrimidin-5-yl)oxy)benzonitrile [280]

To benzylalcohol (46.7 mg, 0.432 mmol) dissolved in CH₃CN (500 μL) wasadded NaH (10.4 mg, 0.432 mmol) and the resulting suspension was stirredfor 10 min. at rt. Then 279 (30 mg, 0.108 mmol 0.0289 mmol) was addedand the reaction mixture was stirred at rt for 2.5 h. MeOH (1 mL) wasadded and stirred for 5 minutes then the reaction mixture wasconcentrated under reduced pressure to give a residue which waspartially purified by preparatory TLC (CH₂Cl₂:MeOH—NH₃ (7 N), 20:1) toafford 28.5 mg of 280. ¹H NMR (500 MHz, CDCl₃): δ 8.21 (s, 1H), 7.58 (d,J=8.9 Hz, 2H), 7.31-7.39 (m, 3H), 7.16-7.18 (m, 2H), 6.94 (d, J=8.8 Hz,2H), 5.45 (s, 2H), 2.60 (s, 3H); ¹³C NMR (125 MHz, CDCl₃): δ 168.2,160.9, 149.8, 140.9, 135.3, 134.1, 133.8, 128.6, 128.5, 128.4, 127.9,127.7, 127.0, 118.6, 116.6, 106.4, 68.6, 14.7; MS (m/z): [M+H]⁺ 350.0.

4-((4-(Benzyloxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)oxy)benzonitrile[281]

280 (35 mg, 0.1 mmol) and m-CPBA (34.4 mg, 0.2 mmol) in CH₂Cl₂ (2 mL)was stirred at rt for 3 h. Then solvent was removed under reducedpressure and the resulting residue was dissolved in DMF (1 mL) andreacted with N-methylpiperazine (26 mg, 0.3 mmol) at 80° C. for 1 h.Solvent was removed under reduced pressure and purified by columnchromatography (CH₂Cl₂:MeOH—NH₃ (7 N), 100:1 to 50:1) to give 26 mg(65%) of 281. ¹H NMR (500 MHz, CDCl₃): δ 7.92 (s, 1H), 7.47 (d, J=7.4Hz, 2H), 7.18-7.21 (m, 3H), 7.06-7.09 (m, 2H), 6.85 (d, J=7.4 Hz, 2H),5.27 (s, 2H), 3.73-3.78 (m, 4H), 2.39-2.43 (m, 4H), 2.29 (s, 3H); ¹³CNMR (125 MHz, CDCl₃): δ 162.1, 161.3, 158.9, 150.8, 136.1, 133.9, 128.4,128.1, 127.6, 127.4, 127.0, 118.8, 116.1, 105.6, 67.7, 54.9, 46.2, 43.1;MS (m/z): [M+H]⁺ 402.2.

4-((4-(Benzyloxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)oxy)benzamide[282]

A mixture of 281 (10 mg, 0.025 mol) and KOH (35 mg, 0.62 mmol) in t-BuOH(500 μL) was heated at 80° C. for 1 h. Solvent was removed under reducedpressure and the residue was purified by preparatory TLC(CH₂Cl₂:MeOH—NH₃ (7 N), 15:1) to afford 8.8 mg (84%) of 282. ¹H NMR (500MHz, CDCl₃): δ 7.93 (s, 1H), 7.66 (d, J=8.8 Hz, 2H), 7.16-7.19 (m, 3H),7.07-7.09 (m, 2H), 6.84 (d, J=8.8 Hz, 2H), 5.83 (br s, 1H), 5.54 (br s,1H), 5.28 (s, 2H), 3.74-3.78 (m, 4H), 2.42-2.45 (m, 4H), 2.30 (s, 3H);¹³C NMR (125 MHz, CDCl₃): δ 168.5, 161.7, 161.5, 158.6, 150.8, 136.3,129.2, 128.3, 128.1, 128.0, 127.5, 127.0, 115.4, 67.6, 54.8, 46.1, 44.0;MS (m/z): [M+H]⁺ 420.2.

Compounds 283 and 284 were synthesized in a similar manner to 282 shownin

4-((4-((4-Methoxybenzyl)oxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)oxy)benzamide[283]

¹H NMR (500 MHz, CDCl₃): δ 7.91 (s, 1H), 7.65 (d, J=8.7 Hz, 2H), 7.04(d, J=8.6 Hz, 2H), 6.82 (d, J=8.7 Hz, 2H), 6.72 (d, J=8.6 Hz, 2H), 5.73(br s, 2H), 5.23 (s, 2H), 3.75 (m, 4H), 3.71 (s, 3H), 2.42 (m, 4H), 2.32(s, 3H); ¹³C NMR (125 MHz, CDCl₃): δ 168.6, 161.7, 161.6, 159.4, 158.6,150.7, 129.4, 129.2, 128.3, 128.1, 127.0, 115.4, 113.7, 67.4, 55.3,54.9, 46.2, 44.1; MS (m/z): [M+H]⁺ 450.2.

4-((4-((3-(Dimethylamino)benzyl)oxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)oxy)benzamide[284]

¹H NMR (500 MHz, CDCl₃): δ 7.92 (s, 1H), 7.64 (d, J=8.7 Hz, 2H), 7.05(t, J=8.6 Hz, 1H), 6.83 (d, J=8.7 Hz, 2H), 6.54 (dd, J=8.0, 2.1 Hz, 1H),6.47 (s, 2H), 5.86 (br s, 1H), 5.48 (br s, 1H), 5.24 (s, 2H), 3.74-3.77(m, 4H), 2.76 (s, 6H), 2.39-2.42 (m, 4H), 2.28 (s, 3H); ¹³C NMR (125MHz, CDCl₃): δ 168.5, 161.7, 161.5, 158.7, 150.7, 150.6, 137.0, 129.2,129.0, 127.9, 126.9, 115.7, 115.3, 112.1, 111.6, 68.1, 54.9, 46.3, 44.2,40.5.

Example 32

(E)-3-(4-Cyanophenyl)acrylic acid [287].A

To a mixture of malonic acid (285; 2.02 g, 19.47 mmol),4-formylbenzonitrile (286; 2.55 g, 19.47 mmol) and pyridine was addedpiperidine (0.2 mL). The reaction mixture was heated at 110° C. for 2 h.Solvent was removed under reduced pressure and the residue was purifiedby column chromatography (CH₂Cl₂: MeOH, 50:1 to 10:1) to afford 3.2 g(95%) of 287. MS m/z [M+H]⁺ 174.3.

(E)-3-(4-Carbamoylphenyl)acrylic acid [288].

A mixture of 287 (3.2 g, 18.5 mmol) and KOH (6.0 g, 107.14 mmol) int-BuOH (50 mL) was heated at 80° C. for 3 h. Solvent was removed underreduced pressure and the residue was purified by column chromatography(CH₂Cl₂: MeOH:CH₃COOH, 15:1:0.1) to afford 2.5 g (72%) of 288. MS m/z[M+H]⁺ 192.3.

(E)-Ethyl 4-(3-ethoxy-3-oxoprop-1-en-1-yl)benzoate [289].

A mixture of 288 (2.5 g, 13.1 mmol) and H₂SO₄ (6.0 g, 107.14 mmol) inEtOH (100 mL) was heated at 80° C. for 12 h. Solvent was removed underreduced pressure and the residue was taken up into CH₂Cl₂ (150 mL) andwashed with water (50 mL) and brine (2×50 mL), dried over MgSO₄,filtered and concentrated to give an oil that was purified by columnchromatography (hexane:EtOAc: 1:1) to afford 0.72 g (23%) of 289. MS m/z[M+H]⁺ 249.1.

Ethyl 4-(3-ethoxy-3-oxopropyl)benzoate [290]

To 289 (0.72 g, 2.90 mmol) in EtOH (50 mL) was added Pd/C (10%) (80 mg)and stirred at room temperature for 12 h. Solvent was removed underreduced pressure and the residue was purified by column chromatography(CH₂Cl₂: MeOH, 50:1 to 10:1) to afford 0.71 g (97%) of 290. MS m/z[M+H]⁺ 251.4.

Ethyl 4-(3-ethoxy-2-formyl-3-oxopropyl)benzoate [291]

A mixture of 290 (0.5 g, 2 mmol) and ethylformate (0.67 g, 9 mmol) in 3mL of THF was added over a period of 30 min to a suspension of NaH (0.1g, 4.1 mmol) in 2 mL THF at 0° C. At the end of addition the reactionmixture was stirred at room temperature for 24 h. Solvent was removedunder reduced pressure and the residue was purified by columnchromatography (hexane: EtOAc, 1:1) to afford 0.43 g (78%) of 291. MSm/z [M+H]⁺ 279.2.

Ethyl 4-((4-hydroxy-2-mercaptopyrimidin-5-yl)methyl)benzoate [292]

A mixture of 291 (0.4 g, 1.43 mmol) and thiourea (0.11 g, 1.43 mmol) in40 mL of EtOH was refluxed for 8 h. Solvent was removed under reducedpressure and the residue was purified by column chromatography (CH₂Cl₂:MeOH:CH₃COOH, 40:1:0.1 to 10:1:0.1) to afford 0.13 g (30%) of 292. MSm/z [M+H]⁺ 291.1.

Ethyl 4-((4-hydroxy-2-(methylthio)pyrimidin-5-yl)methyl)benzoate [293]

To 292 (0.12 g, 0.414 mmol) in DMF (5 mL) was added Et₃N (0.2 mL) andallowed to stir for 10 min. Then to the reaction mixture was addedmethyliodide (62 mg, 0.43 mmol) and the reaction mixture was stirred atrt for 2 h. Solvent was removed under reduced pressure and the residuewas purified by preparative TLC (CH₂Cl₂: MeOH, 10:1) to afford 60 mg(49%) of 293. MS m/z [M+H]⁺ 305.1.

Ethyl 4-((4-chloro-2-(methylthio)pyrimidin-5-yl)methyl)benzoat [294]

A mixture of 293 (60 mg, 0.197 mmol) and POCl₃ (2 mL) were heated at 80°C. for 1 h. After cooling to rt, the reaction mixture was added to abeaker containing ice chips. Following complete quenching of POCl₃,solid Na₂CO₃ was carefully added until pH˜9. This was transferred to aseperatory funnel and extracted with CH₂Cl₂ (4×25 mL), dried over MgSO₄,filtered and concentrated to a solid which was purified by preparativeTLC (hexane:EtOAc, 8:2) to afford 56 mg (88%) of 294. MS (m/z): [M+H]⁺323.0/325.0.

Ethyl 4-((4-(benzyloxy)-2-(methylthio)pyrimidin-5-yl)methyl)benzoate[295]

To benzyl alcohol (10.7 μL, 11.3 mg, 0.104 mmol) dissolved in CH₃CN (500μL) was added NaH (2.8 mg, 0.116 mmol) and the resulting suspension wasstirred for 10 min. at rt. Then 294 (28 mg, 0.0869 mmol) was added andthe reaction mixture was stirred at rt for 2.5 h. MeOH (1 mL) was addedand stirred for 5 minutes then the reaction mixture was concentratedunder reduced pressure to give a residue which was purified bypreparatory TLC (CH₂Cl₂:MeOH—NH₃ (7 N), 20:1) to afford 31.2 mg (91%) of295. (MS (m/z): [M+H]⁺ 395.2.

4-((4-(Benzyloxy)-2-(methylthio)pyrimidin-5-yl)methyl)benzoic acid [296]

A mixture of 295 (31 mg, 0.0786 mmol) and NaOH (9.5 mg, 0.236 mmol) in10 mL of EtOH was refluxed for 8 h. Solvent was removed under reducedpressure and the residue was used in the next step without furtherpurification. MS m/z [M+H]⁺ 367.1.

4-((4-(Benzyloxy)-2-(methylthio)pyrimidin-5-yl)methyl)benzamide [297]

To 296 (28 mg, 0.0765 mmol) in DMF (2 mL) was added oxalyl chloride (6.6μL, 9.6 mg, 0.0765 mmol) at rt and allowed to stir for 5 h resulting inacid chloride. Then to the reaction mixture NH₃ (g) was bubbled at −78°C. and the reaction mixture was stirred at room temperature for 30 min.Solvent was removed under reduced pressure and the residue was purifiedby preparative TLC (CH₂Cl₂: MeOH—NH₃ (7 N), 20:1) to afford 24 mg (86%)of 297. MS m/z [M+H]⁺ 366.2.

4-((4-(Benzyloxy)-2-(methylsulfonyl)pyrimidin-5-yl)methyl)benzamide[298]

To 297 (24 mg, 0.0655 mmol) in CH₂Cl₂ (5 mL) was added m-CPBA (22.6 mg,0.1314 mmol) and allowed to stir for 2 h at rt. Solvent was removedunder reduced pressure and the resulting sulfone was further reactedwithout additional purification. MS m/z [M+H]⁺ 398.1.

4-((4-(Benzyloxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)methyl)benzamide[299]

To a solution of 298 (26 mg, 0.0656 mmol) in DMF (2 mL) was addedN-methylpiperazine (20.5 μL, 18.1 mg, 0.181 mmol) and K₂CO₃ (7.3 mg,0.1312 mmol) and heated at 100° C. for 1 h. Solvent was removed underreduced pressure and the residue was was purified by preparative TLC(CH₂Cl₂:MeOH—NH₃ (7 N), 20:1) to afford 20 mg (69%) of 299. ¹H NMR (500MHz, CDCl₃): δ 7.86 (s, 1H), 7.60 (d, J=8.2 Hz, 2H), 7.12-7.23 (m, 7H),5.24 (s, 2H), 3.64-3.75 (m, 6H), 2.34-2.41 (m, 4H), 2.26 (s, 3H); ¹³CNMR (125 MHz, CDCl₃): δ 169.1, 167.1, 160.9, 157.5, 144.9, 136.8, 131.0,128.9, 128.4, 127.9, 127.7, 127.4, 108.4, 67.3, 54.9, 46.2, 43.9, 32.8;MS m/z [M+H]⁺ 418.1.

Example 33

Ethyl4-((4-((4-cyanobenzyl)oxy)-2-(methylthio)pyrimidin-5-yl)methyl)benzoate[300]

To 4-cyanobenzylalcohol (11.9 μL, 13.8 mg, 0.104 mmol) dissolved inCH₃CN (500 μL) was added NaH (2.8 mg, 0.116 mmol) and the resultingsuspension was stirred for 10 min. at rt. Then 294 (28 mg, 0.0869 mmol)was added and the reaction mixture was stirred at rt for 2.5 h. MeOH (1mL) was added and stirred for 5 minutes then the reaction mixture wasconcentrated under reduced pressure to give a residue which was purifiedby preparatory TLC (CH₂Cl₂:MeOH—NH₃ (7 N), 20:1) to afford 29.2 mg (81%)of 300 (MS (m/z): [M+H]⁺ 420.2.

4-((4-((4-Cyanobenzyl)oxy)-2-(methylthio)pyrimidin-5-yl)methyl)benzoicacid [301]

A mixture of 300 (29 mg, 0.0692 mmol) and NaOH (8.3 mg, 0.2076 mmol) in10 mL of EtOH was refluxed for 8 h. Solvent was removed under reducedpressure and the residue was used in the next step without furtherpurification. MS m/z [M+H]⁺ 392.1.

4-((4-((4-Cyanobenzyl)oxy)-2-(methylthio)pyrimidin-5-yl)methyl)benzamide[302]

To 301 (27 mg, 0.069 mmol) in DMF (2 mL) was added oxalyl chloride (5.9μL, 8.7 mg, 0.069 mmol) at rt and allowed to stir for 5 h resulting inacid chloride. Then to the reaction mixture NH₃ (g) was bubbled at −78°C. and the reaction mixture was stirred at room temperature for 30 min.Solvent was removed under reduced pressure and the residue was purifiedby preparative TLC (CH₂Cl₂: MeOH—NH₃ (7 N), 20:1) to afford 23 mg (85%)of 302. MS m/z [M+H]⁺ 391.2.

4-((4-((4-Cyanobenzyl)oxy)-2-(methylsulfonyl)pyrimidin-5-yl)methyl)benzamide[303]

To 302 (23 mg, 0.0588 mmol) in CH₂Cl₂ (5 mL) was added m-CPBA (20.2 mg,0.1176 mmol) and allowed to stir for 2 h at rt. Solvent was removedunder reduced pressure and the resulting sulfone was further reactedwithout additional purification. MS m/z [M+H]⁺ 423.1.

4-((4-((4-Cyanobenzyl)oxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)methyl)benzamide[304]

To a solution of 303 (25 mg, 0.0591 mmol) in DMF (2 mL) was addedN-methylpiperazine (19.7 μL, 17.7 mg, 0.177 mmol) and K₂CO₃ (6.6 mg,0.1182 mmol) and the mixture was heated at 100° C. for 1 h. Solvent wasremoved under reduced pressure and the residue was was purified bypreparative TLC (CH₂Cl₂:MeOH—NH₃ (7 N), 20:1) to afford 17 mg (65%) of304. ¹H NMR (500 MHz, CDCl₃): δ 7.87 (s, 1H), 7.66 (d, J=8.4 Hz, 2H),7.51 (d, J=8.4 Hz, 2H), 7.18 (d, J=8.4 Hz, 2H), 7.16 (d, J=8.4 Hz, 2H),5.29 (s, 2H), 3.75 (s, 2H), 3.66-3.71 (m, 4H), 2.37-2.43 (m, 4H), 2.27(s, 3H); MS m/z [M+H]⁺ 443.1.

Example 34

tert-Butyl 4-acetylpiperazine-1-carboxylate [306].

To a solution of 305 (1 g, 5.36 mmol) in CH₂Cl₂ (10 mL) cooled to 0° C.was added acetic anhydride (557 μL, 5.9 mmol) over a period of twominutes. The reaction mixture was stirred at 0° C. for 30 minutes. Thesolvent was removed under reduced pressure and the crude was treatedwith saturated NaHCO₃ (40 mL) and extracted with diethyl ether (3×30mL). The combined organic extracts were dried over MgSO₄ and the solventwas concentrated to give 0.86 g (70%) of 306 as a clear oil that wasused without further purification. MS (m/z): [M+Na]⁺ 251.5.

tert-Butyl 4-(1-methylcyclopropyl)piperazine-1-carboxylate [307]

306 (850 mg, 3.72 mmol) is dissolved in dry THF (10 mL) and cooled to−78° C. under argon. To this was added a solution of MeTi(O-i-Pr)₃ (4.5mL of 1M in THF) over a period of 3 minutes followed by EtMgBr (4.8 mLof 3M in Et₂O) over a period of 7 minutes. The reaction mixture wasallowed to warm to rt and stirred for an additional 30 minutes thencarefully diluted with water (10 mL) and a solution of Rochelle salt (30mL, 20% aq.). The mixture was stirred vigorously for 15 minutes thenextracted with EtOAc (3×) and the combined organic layers were driedunder MgSO₄. Solvent was removed under reduced pressure and the residuewas purified by chromatography (0-20% EtOAc in hexanes) to afford 307(0.358 g, 40%). MS (m/z): [M+H]⁺ 241.1.

1-(1-Methylcyclopropyl)piperazine [308]

To a solution of 307 (300 mg, 1.24 mmol) in CH₂Cl₂ (6 mL) was added TFA(800 μL) and the reaction mixture was stirred at rt for 24 h. Thesolvent was concentrated to give 308 as its diTFA salt in quantitativeyield and used without any further purification. MS (m/z): [M+H]⁺ 141.8.

Example 35

4-((4-((3-Methoxybenzyl)oxy)-2-(4-(1-methylcyclopropyl)piperazin-1-yl)pyrimidin-5-yl)thio)benzonitrile[310]

To 309 (8.2 mg, 0.021 mmol) was added 308 (106.6 mg, 0.29 mmol) and Et₃N(50 μL) in DMF (1 mL) and heated at 90° C. for 2 h. Solvent was removedunder reduced pressure and the residue was purified by preparatory TLC(hexane:EtOAc, 8:2) to afford 8.6 mg (84%) of 310. MS (ESI) m/z [M+H]⁺488.2.

4-((2-(4-(2-Cyclopropylpropan-2-yl)piperazin-1-yl)-4-((3-methoxybenzyl)oxy)pyrimidin-5-yl)thio)benzonitrile[312]

To 309 (10 mg, 0.026 mmol) was added1-(2-cyclopropylpropan-2-yl)piperazine (8.8 mg, 0.052 mmol) in DMF (1.5mL) and heated at 90° C. for 1 h. Solvent was removed under reducedpressure and the residue was purified by preparatory TLC (CH₂Cl₂:MeOH,40:1) to afford 6 mg (45%) of 312. MS (ESI) m/z [M+H]⁺ 516.2.

(S)-4-((2-(4-(1-Cyclopropylethyl)piperazin-1-yl)-4-((3-methoxybenzyl)oxy)pyrimidin-5-yl)thio)benzonitrile[314]

To 309 (10 mg, 0.026 mmol) was added(S)-1-(1-cyclopropylethyl)piperazine (20.1 mg, 0.130 mmol) in DMF (2 mL)and heated at 90° C. for 1 h. Solvent was removed under reduced pressureand the residue was purified by preparatory TLC (CH₂Cl₂:MeOH, 40:1) toafford 12 mg (92%) of 314. MS (ESI) m/z [M+H]⁺ 502.2.

(R)-4-((2-(4-(1-Cyclopropylethyl)piperazin-1-yl)-4-((3-methoxybenzyl)oxy)pyrimidin-5-yl)thio)benzonitrile[316]

To 309 (10 mg, 0.026 mmol) was added(R)-1-(1-cyclopropylethyl)piperazine (20.1 mg, 0.130 mmol) in DMF (2 mL)and heated at 90° C. for 1 h. Solvent was removed under reduced pressureand the residue was purified by preparatory TLC (CH₂Cl₂:MeOH, 40:1) toafford 8.5 mg (65%) of 316. MS (ESI) m/z [M+H]⁺ 502.2.

4-((4-((3-Methoxybenzyl)oxy)-2-(3-oxopiperazin-1-yl)pyrimidin-5-yl)thio)benzonitrile[318]

To 309 (11.1 mg, 0.0289 mmol) was added piperizine-2-one (14.5 mg, 0.145mmol) and Et₃N (21 μL, 0.145 mmol) in DMF (1 mL) and heated at 90° C.for 1 h. Solvent was removed under reduced pressure and the residue waspurified by preparatory TLC (CH₂Cl₂:MeOH, 20:1) to afford 9.7 mg (75%)of 318. MS (ESI) m/z [M+H]⁺ 448.0.

4-((2-(4-(Cyclopropylmethyl)-3-oxopiperazin-1-yl)-4-((3-methoxybenzyl)oxy)pyrimidin-5-yl)thio)benzonitrile[320]

To 309 (9.9 mg, 0.0258 mmol) was added1-(cyclopropylmethyl)piperazin-2-one (36 mg, 0.129 mmol) and Et₃N (50μL) in DMF (1 mL) and heated at 90° C. for 1 h. Solvent was removedunder reduced pressure and the residue was purified by preparatory TLC(CH₂Cl₂:MeOH, 20:1) to afford 10.3 mg (80%) of 320. MS (ESI) m/z [M+H]⁺502.0.

4-((4-((3-Methoxybenzyl)oxy)-2-(4-(oxazol-2-ylmethyl)piperazin-1-yl)pyrimidin-5-yl)thio)benzonitrile[322]

To 309 (13.8 mg, 0.0360 mmol) was added 2-(piperazin-1-ylmethyl)oxazole(30.1 mg, 0.18 mmol) and Et₃N (50 μL) in DMF (1 mL) and heated at 90° C.for 1 h. Solvent was removed under reduced pressure and the residue waspurified by preparatory TLC (CH₂Cl₂:MeOH, 40:1) to afford 15.5 mg (84%)of 322. MS (ESI) m/z [M+H]⁺ 515.1.

4-((4-((3-Methoxybenzyl)oxy)-2-(4-(4-((tetrahydro-2H-pyran-2-yl)oxy)but-2-yn-1-yl)piperazin-1-yl)pyrimidin-5-yl)thio)benzonitrile[324]

To 309 (14.9 mg, 0.0389 mmol) was added1-(4-((tetrahydro-2H-pyran-2-yl)oxy)but-2-yn-1-yl)piperazine (37.1 mg,0.1995 mmol) and Et₃N (50 μL) in DMF (1 mL) and heated at 90° C. for 1h. Solvent was removed under reduced pressure and the residue waspurified by preparatory TLC (hexane:EtOAc, 1:4) to afford 12.3 mg (54%)of 324. MS (ESI) m/z [M+H]⁺ 586.1.

4-((4-((3-Methoxybenzyl)oxy)-2-(4-(1-methylcyclopropyl)piperazin-1-yl)pyrimidin-5-yl)thio)benzamide[311]

A mixture of 310 (8.6 mg, 0.0176 mmol) and KOH (19.7 mg, 0.352 mmol) int-BuOH (1.5 mL) was heated at 80° C. for 1 h. Solvent was removed underreduced pressure and the residue was purified by preparatory TLC(CH₂Cl₂:MeOH—NH₃ (7 N), 20:1) to afford 6.1 mg (68%) of 311. ¹H NMR (600MHz, CDCl₃): δ 8.30 (s, 1H), 7.64 (d, J=8.3 Hz, 2H), 7.19 (t, J=7.9 Hz,1H), 7.14 (d, J=8.3 Hz, 2H), 6.80 (d, J=8.3 Hz, 1H), 6.73 (d, J=7.6 Hz,1H), 6.62 (s, 1H), 6.49 (br s, 1H), 6.25 (br s, 1H), 5.44 (s, 2H), 4.89(m, 2H), 3.71 (s, 3H), 3.53 (m, 4H), 3.09 (m, 2H), 1.59 (t, J=6.1 Hz,2H), 1.37 (s, 3H), 0.78 (t, J=6.2 Hz, 2H); ¹³C NMR (150 MHz, CDCl₃): δ170.0, 168.8, 164.4, 161.4, 160.8, 159.6, 143.3, 137.5, 129.5, 127.9,126.4, 119.6, 113.3, 113.1, 100.5, 68.2, 55.2, 49.2, 43.8, 40.8, 15.8,12.7; HRMS (ESI) m/z [M+H]⁺ calcd. for C₇H₃₂N₅O₃S, 506.2226; found506.2208.

4-((2-(4-(2-Cyclopropylpropan-2-yl)piperazin-1-yl)-4-((3-methoxybenzyl)oxy)pyrimidin-5-yl)thio)benzamide[313]

A mixture of 312 (6 mg, 0.0116 mmol) and KOH (13 mg, 0.232 mmol) int-BuOH (2 mL) was heated at 70° C. for 1.5 h. Solvent was removed underreduced pressure and the residue was purified by preparatory TLC(CH₂Cl₂:MeOH—NH₃ (7 N), 20:1) to afford 5.8 mg (94%) of 313. ¹H NMR (600MHz, CDCl₃): δ 8.26 (s, 1H), 7.62 (d, J=8.4 Hz, 2H), 7.17 (t, J=7.9 Hz,1H), 7.11 (d, J=8.5 Hz, 2H), 6.79 (d, J=8.2 Hz, 1H), 6.76 (d, J=7.5 Hz,1H), 6.69 (s, 1H), 6.04 (br s, 1H), 5.50 (br s, 1H), 5.34 (s, 2H), 3.87(m, 4H), 3.68 (s, 3H), 2.77 (m, 4H), 1.22 (m, 1H), 0.88 (s, 6H), 0.45(m, 2H), 0.25 (m, 2H); HRMS (ESI) m/z [M+H]⁺ calcd. for C₂₉H₃₆N₅O₃S,534.2539; found 534.2537.

(S)-4-((2-(4-(1-Cyclopropylethyl)piperazin-1-yl)-4-((3-methoxybenzyl)oxy)pyrimidin-5-yl)thio)benzamide[315]

A mixture of 314 (12 mg, 0.0239 mmol) and KOH (27 mg, 0.478 mmol) int-BuOH (2 mL) was heated at 80° C. for 1 h. Solvent was removed underreduced pressure and the residue was purified by preparatory TLC(CH₂Cl₂:MeOH—NH₃ (7 N), 20:1) to afford 12 mg (97%) of 315. ¹H NMR (600MHz, CDCl₃): δ 8.26 (s, 1H), 7.62 (d, J=8.8 Hz, 2H), 7.17 (t, J=6.6 Hz,1H), 7.11 (d, J=8.8 Hz, 2H), 6.74-6.80 (m, 2H), 6.69 (s, 1H), 6.03 (brs, 1H), 5.60 (br s, 1H), 5.34 (s, 2H), 3.89 (m, 4H), 3.68 (s, 3H), 2.81(m, 2H), 2.64 (m, 2H), 1.72 (m, 1H), 1.20 (d, J=6.5 Hz, 3H), 0.73-0.80(m, 1H), 0.59-0.67 (m, 1H), 0.46-0.53 (m, 1H), 0.27-0.34 (m, 1H),0.01-0.08 (m, 1H); HRMS (ESI) m/z [M+H]⁺ calcd. for C₂₈H₃₄N₅O₃S,520.2382; found 520.2360.

(R)-4-((2-(4-(1-Cyclopropylethyl)piperazin-1-yl)-4-((3-methoxybenzyl)oxy)pyrimidin-5-yl)thio)benzamide[317]

A mixture of 316 (8.5 mg, 0.0169 mmol) and KOH (19 mg, 0.338 mmol) int-BuOH (2 mL) was heated at 80° C. for 1 h. Solvent was removed underreduced pressure and the residue was purified by preparatory TLC(CH₂Cl₂:MeOH—NH₃ (7 N), 20:1) to afford 8 mg (91%) of 317. ¹H NMR (600MHz, CDCl₃): δ 8.26 (s, 1H), 7.62 (d, J=6.8 Hz, 2H), 7.17 (t, J=7.9 Hz,1H), 7.11 (d, J=8.7 Hz, 2H), 6.79 (dd, J=8.2, 2.5 Hz, 1H), 6.76 (d,J=7.6 Hz, 1H), 6.69 (s, 1H), 6.01 (br s, 1H), 5.51 (br s, 1H), 5.34 (s,2H), 3.89 (m, 4H), 3.68 (s, 3H), 2.81 (m, 2H), 2.64 (m, 2H), 1.72 (m,1H), 1.21 (m, 3H), 0.77 (m, 1H), 0.63 (m, 1H), 0.49 (m, 1H), 0.31 (m,1H), 0.05 (m, 1H); HRMS (ESI) m/z [M+H]⁺ calcd. for C₂₈H₃₄N₅O₃S,520.2382; found 520.2396.

4-((4-((3-Methoxybenzyl)oxy)-2-(3-oxopiperazin-1-yl)pyrimidin-5-yl)thio)benzamide[319]

A mixture of 318 (9.7 mg, 0.0217 mmol) and KOH (24.3 mg, 0.433 mmol) int-BuOH (2 mL) was heated at 70° C. for 1.5 h. Solvent was removed underreduced pressure and the residue was purified by preparatory TLC(CH₂Cl₂:MeOH—NH₃ (7 N), 10:1) to afford 6.6 mg (65%) of 319. ¹H NMR (600MHz, MeOH-d₄): δ 8.23 (s, 1H), 7.63 (d, J=6.7 Hz, 2H), 7.05 (t, J=7.8Hz, 1H), 7.02 (d, J=6.7 Hz, 2H), 6.66-6.70 (m, 1H), 6.64 (d, J=7.6 Hz,1H), 6.60 (s, 1H), 5.27 (s, 2H), 4.30 (s, 2H), 3.94-3.98 (m, 2H), 3.55(s, 3H), 3.28-3.33 (m, 2H); ¹³C NMR (150 MHz, MeOH-d₄): 171.7, 170.6,170.2, 165.9, 162.3, 161.2, 144.3, 139.3, 131.8, 130.4, 129.3, 126.9,120.7, 114.5, 113.8, 100.9, 69.2, 55.6, 49.6, 41.6, 41.4; HRMS (ESI) m/z[M+H]⁺ calcd. for C₂₃H₂₄N₅O₄S, 466.1549; found 466.1550.

4-((2-(4-(Cyclopropylmethyl)-3-oxopiperazin-1-yl)-4-((3-methoxybenzyl)oxy)pyrimidin-5-yl)thio)benzamide[321]

A mixture of 320 (10.3 mg, 0.0205 mmol) and KOH (23.1 mg, 0.411 mmol) int-BuOH (2 mL) was heated at 70° C. for 1.5 h. Solvent was removed underreduced pressure and the residue was purified by preparatory TLC(CH₂Cl₂:MeOH—NH₃ (7 N), 20:1) to afford 6.6 mg (62%) of 321. ¹H NMR (600MHz, CDCl₃): δ 8.31 (s, 1H), 7.64 (d, J=8.4 Hz, 2H), 7.17 (t, J=9.5 Hz,1H), 7.12 (d, J=8.0 Hz, 2H), 6.74-6.80 (m, 2H), 6.68 (s, 1H), 6.00 (brs, 1H), 5.50 (br s, 1H), 5.41 (s, 2H), 4.48 (s, 2H), 4.10-4.13 (m, 2H),3.73 (s, 3H), 3.52-3.56 (m, 2H), 3.37 (d, J=7.0 Hz, 2H), 0.98-1.04 (m,1H), 0.50-0.58 (m, 2H), 0.27-0.31 (m, 2H); ¹³C NMR (150 MHz, CDCl₃):168.7, 168.6, 165.5, 164.8, 160.6, 159.6, 143.1, 137.9, 130.1, 129.4,127.8, 126.1, 119.7, 113.5, 112.9, 99.4, 67.9, 55.2, 51.1, 48.2, 45.9,40.9, 9.1, 3.6; HRMS (ESI) m/z [M+H]⁺ calcd. for C₂₇H₃₀N₅O₄S, 520.2019;found 520.1994.

4-((4-((3-Methoxybenzyl)oxy)-2-(4-(oxazol-2-ylmethyl)piperazin-1-yl)pyrimidin-5-yl)thio)benzamide[323]

A mixture of 322 (15.5 mg, 0.0301 mmol) and KOH (16.9 mg, 0.301 mmol) int-BuOH (2 mL) was heated at 70° C. for 1.5 h. Solvent was removed underreduced pressure and the residue was purified by preparatory TLC(CH₂Cl₂:MeOH—NH₃ (7 N), 15:1) to afford 10 mg (63%) of 323. ¹H NMR (600MHz, CDCl₃): δ 8.26 (s, 1H), 7.67 (s, 1H), 7.61 (d, J=8.4 Hz, 2H), 7.16(t, J=7.8 Hz, 1H), 7.08-7.13 (m, 3H), 6.78 (d, J=8.2 Hz, 1H), 6.74 (d,J=7.5 Hz, 1H), 6.66 (s, 1H), 6.06 (br s, 1H), 5.63 (br s, 1H), 5.32 (s,2H), 3.90-3.93 (m, 4H), 3.79 (s, 2H), 3.68 (s, 3H), 2.61-2.64 (m, 4H);¹³C NMR (150 MHz, CDCl₃): 168.8, 168.6, 164.9, 161.5, 160.9, 159.5,143.5, 139.2, 139.8, 129.9, 129.3, 127.7, 127.2, 125.9, 119.7, 113.2,113.1, 97.9, 67.6, 55.1, 54.7, 52.6, 43.7; HRMS (ESI) m/z [M+H]⁺ calcd.for C₂₇H₂₉N₆O₄S, 533.1971; found 533.1979.

4-((4-((3-Methoxybenzyl)oxy)-2-(4-(4-((tetrahydro-2H-pyran-2-yl)oxy)but-2-yn-1-yl)piperazin-1-yl)pyrimidin-5-yl)thio)benzamide[325]

A mixture of 324 (12.3 mg, 0.0210 mmol) and KOH (11.8 mg, 0.210 mmol) int-BuOH (2 mL) was heated at 70° C. for 1.5 h. Solvent was removed underreduced pressure and the residue was purified by preparatory TLC(CH₂Cl₂:MeOH—NH₃ (7 N), 15:1) to afford 7.6 mg (60%) of 325. MS (ESI)m/z [M+H]⁺ 604.1.

Example 36

4-((2-(4-(4-Hydroxybut-2-yn-1-yl)piperazin-1-yl)-4-((3-methoxybenzyl)oxy)pyrimidin-5-yl)thio)benzamide[326]

A mixture of 325 (7.6 mg, 0.0126) in EtOH (1 mL) was added PPTS (1 mg,0.004 mmol) and the reaction stirred at 60° C. for overnight. Solventwas removed under reduced pressure and the residue was purified bypreparatory TLC (CH₂Cl₂:MeOH—NH₃ (7 N), 10:1) to afford 3.7 mg (57%) of326. ¹H NMR (600 MHz, CDCl₃/MeOH-d₄): δ 8.24 (s, 1H), 7.72 (d, J=8.6 Hz,1H), 7.16 (t, J=7.9 Hz, 1H), 7.12 (d, J=8.6 Hz, 2H), 6.78 (d, J=8.2 Hz,1H), 6.74 (d, J=7.5 Hz, 1H), 6.70 (s, 1H), 5.34 (s, 2H), 4.23 (s, 2H),3.90-3.93 (m, 4H), 3.67 (s, 3H), 3.41 (t, J=1.7 Hz, 2H), 2.65-2.68 (m,4H); ¹³C NMR (150 MHz, CDCl₃/MeOH-d₄): 171.7, 170.2, 166.1, 162.9,161.1, 144.7, 139.4, 131.5, 130.6, 129.3, 126.9, 120.9, 114.6, 113.9,99.9, 85.7, 79.9, 69.1, 55.9, 52.9, 51.0, 48.1, 44.8; HRMS (ESI) m/z[M+H]⁺ calcd. for C₂₇H₃₀N₅O₄S, 520.2019; found 520.2003.

Example 37

4-((4-((3-Methylbenzyl)oxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)-2-(trifluoromethyl)benzonitrile[328]

To a solution of m-tolylmethanol (20.5 μL, 0.170 mmol) in CH₃CN (1 mL)was added NaH (3.5 mg, 0.148 mmol) and the resulting suspension wasstirred for 10 min. at rt. Then 327 (15.6 mg, 0.037 mmol) was added andthe reaction mixture was stirred at rt for 3 h. The reaction mixture wasconcentrated under reduced pressure to give a residue which was purifiedby preparatory TLC (CH₂Cl₂:MeOH—NH₃ (7 N), 20:1) to afford 7.5 mg (41%)of 328. MS (ESI) m/z [M+H]⁺ 500.0.

4-((4-((3-Isopropylbenzyl)oxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)-2-(trifluoromethyl)benzonitrile[330]

To a solution of (3-isopropylphenyl)methanol (17.9 mg, 0.119 mmol) inCH₃CN (1 mL) was added NaH (2.5 mg, 0.106 mmol) and the resultingsuspension was stirred for 10 min. at rt. Then 327 (11 mg, 0.0265 mmol)was added and the reaction mixture was stirred at rt for 3 h. Thereaction mixture was concentrated under reduced pressure to give aresidue which was purified by preparatory TLC (CH₂Cl₂:MeOH—NH₃ (7 N),20:1) to afford 13.5 mg (97%) of 330. MS(ESI) m/z [M+H]⁺ 528.2.

4-((4-((3-Ethylbenzyl)oxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)-2-(trifluoromethyl)benzonitrile[332]

To (3-ethylphenyl)methanol (16.2 mg, 0.119 mmol) dissolved in CH₃CN (1mL) was added NaH (2.5 mg, 0.106 mmol) and the resulting suspension wasstirred for 10 min. at rt. Then 327 (11 mg, 0.0265 mmol) was added andthe reaction mixture was stirred at rt for 3 h. The reaction mixture wasconcentrated under reduced pressure to give a residue which was purifiedby preparatory TLC (CH₂Cl₂:MeOH—NH₃ (7 N), 20:1) to afford 9.4 mg (69%)of 332. MS (ESI) m/z [M+H]⁺ 514.2.

4-((4-((3-Methylbenzyl)oxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)-2-(trifluoromethyl)benzamide[329]

A mixture of 328 (7.5 mg, 0.015 mmol) and KOH (16.8 mg, 0.30 mmol) int-BuOH (2 mL) was heated at 80° C. for 1 h. Solvent was removed underreduced pressure and the residue was purified by preparatory TLC(CH₂Cl₂:MeOH—NH₃ (7 N), 20:1) to afford 4.7 mg (61%) of 329. ¹H NMR (600MHz, CDCl₃): δ 8.26 (s, 1H), 7.45 (s, 1H), 7.41 (d, J=8.2 Hz, 1H), 7.20(d, J=8.1 Hz, 1H), 7.17 (t, J=7.6 Hz, 1H), 7.07 (d, J=7.6 Hz, 1H), 7.02(s, 1H), 6.96 (d, J=7.6 Hz, 1H), 5.68-5.80 (m, 2H), 5.32 (s, 2H), 3.90(m, 4H), 2.49 (m, 4H), 2.37 (s, 3H), 2.28 (s, 3H); ¹³C NMR (150 MHz,CDCl₃): δ 169.0, 168.6, 164.9, 161.7, 142.3, 138.0, 136.1, 131.3, 129.2,129.1, 128.7, 128.32, 128.28, 127.6 (q, J=31.9 Hz), 123.9 (q, J=5.1 Hz),123.2 (q, J=272.5 Hz), 97.0, 68.0, 54.7, 46.2, 43.8, 21.4; HRMS (ESI)m/z [M+H]⁺ calcd. for C₂₅H₂₇F₃N₅O₂S, 518.1838; found 518.1834.

4-((4-((3-Isopropylbenzyl)oxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)-2-(trifluoromethyl)benzamide[331]

A mixture of 330 (13.5 mg, 0.0255 mmol) and KOH (28.6 mg, 0.511 mmol) int-BuOH (2 mL) was heated at 80° C. for 1 h. Solvent was removed underreduced pressure and the residue was purified by preparatory TLC(CH₂Cl₂:MeOH—NH₃ (7 N), 20:1) to afford 7.8 mg (56%) of 331. ¹H NMR (600MHz, CDCl₃): δ 8.27 (s, 1H), 7.46 (s, 1H), 7.41 (d, J=8.2 Hz, 1H), 7.20(t, J=7.8 Hz, 2H), 7.10-7.15 (m, 2H), 6.97 (d, J=7.6 Hz, 1H), 5.80 (brs, 1H), 5.73 (br s, 1H), 5.35 (s, 2H), 3.90 (m, 4H), 2.83 (septet, J=6.9Hz, 1H), 2.49 (m, 4H), 2.36 (s, 3H), 1.19 (d, J=6.9 Hz, 6H); ¹³C NMR(150 MHz, CDCl₃): δ 169.1, 168.7, 165.0, 161.8, 149.0, 142.4, 136.2,131.3, 129.2, 129.0, 128.4, 127.7 (q, J=31.8 Hz), 126.0, 125.5, 124.8,123.8 (q, J=5.3 Hz), 123.2 (q, J=272.3 Hz), 96.9, 68.2, 54.7, 46.2,43.8, 34.0, 23.9; HRMS (ESI) m/z [M+H]⁺ calcd. for C₂₇H₃₁F₃N₅O₂S,546.2151; found 546.2159.

4-((4-((3-Ethylbenzyl)oxy)-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)thio)-2-(trifluoromethyl)benzamide[333]

A mixture of 332 (9.4 mg, 0.0183 mmol) and KOH (21 mg, 0.366 mmol) int-BuOH (1.5 mL) was heated at 80° C. for 1 h. Solvent was removed underreduced pressure and the residue was purified by preparatory TLC(CH₂Cl₂:MeOH—NH₃ (7 N), 20:1) to afford 5 mg (52%) of 333. ¹H NMR (600MHz, CDCl₃): δ 8.27 (s, 1H), 7.45 (s, 1H), 7.41 (d, J=8.1 Hz, 1H),7.16-7.23 (m, 2H), 7.10 (d, J=7.6 Hz, 1H), 7.07 (s, 1H), 6.97 (d, J=7.6Hz, 1H), 5.77 (br s, 1H), 5.72 (br s, 1H), 5.34 (s, 2H), 3.90 (m, 4H),2.58 (q, J=7.6 Hz, 2H), 2.49 (m, 4H), 2.37 (s, 3H), 1.18 (t, J=7.6 Hz,3H); ¹³C NMR (150 MHz, CDCl₃): δ 169.0, 168.7, 165.0, 161.7, 144.4,142.3, 136.2, 131.3, 129.14, 129.08, 128.4, 127.7 (q, J=31.9 Hz), 127.5,127.0, 124.7, 123.8 (q, J=5.3 Hz), 123.2 (q, J=272.3 Hz), 97.0, 68.1,54.7, 46.1, 43.8, 28.7, 15.5; HRMS (ESI) m/z [M+H]⁺ calcd. forC₂₆H₂₉F₃N₅O₂S, 532.1994; found 532.1994.

Example 38

4-((4-((3-(Dimethylamino)benzyl)oxy)-2-(4-(prop-2-yn-1-yl)piperazin-1-yl)pyrimidin-5-yl)thio)benzonitrile[335]

To 334 (16.5 mg, 0.0416 mmol) was added 1-(prop-2-yn-1-yl)piperazine (46mg, 0.208 mmol) and Et₃N (75 μL) in DMF (1 mL) and heated at 90° C. for1 h. Solvent was removed under reduced pressure and the residue waspurified by preparatory TLC (CH₂Cl₂:MeOH, 40:1) to afford 14.4 mg (71%)of 335. MS (ESI) m/z [M+H]⁺ 485.1.

4-((4-((3-(Dimethylamino)benzyl)oxy)-2-(4-(prop-2-yn-1-yl)piperazin-1-yl)pyrimidin-5-yl)thio)benzamide[336]

A mixture of 335 (14.4 mg, 0.03 mmol) and KOH (33.3 mg, 0.594 mmol) int-BuOH (2 mL) was heated at 80° C. for 1.5 h. Solvent was removed underreduced pressure and the residue was purified by preparatory TLC(CH₂Cl₂:MeOH—NH₃ (7N), 20:1) to afford 10.9 mg (73%) of 336. ¹H NMR (600MHz, CDCl₃): δ 8.26 (s, 1H), 7.59 (d, J=8.4 Hz, 2H), 7.12 (t, J=7.9 Hz,1H), 7.07 (d, J=7.7 Hz, 2H), 6.62 (d, J=8.3 Hz, 1H), 6.58 (s, 1H), 6.54(d, J=7.4 Hz, 1H), 6.02 (br s, 1H), 5.58 (br s, 1H), 5.34 (s, 2H),3.91-3.94 (m, 4H), 3.38 (s, 2H), 2.81 (s, 6H), 2.63-2.67 (m, 4H), 2.29(t, J=2.3 Hz, 1H); ¹³C NMR (150 MHz, CDCl₃): δ 168.8, 168.7, 164.9,161.7, 150.6, 143.7, 137.1, 129.6, 129.0, 127.7, 125.7, 115.7, 112.1,111.7, 97.8, 78.4, 73.7, 68.3, 51.6, 47.0, 43.9, 40.6; MS (ESI) m/z[M+H]⁺ 503.1.

Example 39

4-((4-((3-(Dimethylamino)benzyl)oxy)-2-(4-(prop-2-yn-1-yl)piperazin-1-yl)pyrimidin-5-yl)thio)-2-(trifluoromethyl)benzonitrile[338]

To 337 (23.2 mg, 0.05 mmol) was added 1-(prop-2-yn-1-yl)piperazine (88mg, 0.250 mmol) and Et₃N (50 μL) in DMF (1 mL) and heated at 90° C. for1 h. Solvent was removed under reduced pressure and the residue waspurified by preparatory TLC (CH₂Cl₂:MeOH, 20:1) to afford 19.7 mg (72%)of 338. MS (ESI) m/z [M+H]⁺ 553.0.

4-((2-(4-Cyclopropylpiperazin-1-yl)-4-((3-(dimethylamino)benzyl)oxy)pyrimidin-5-yl)thio)-2-(trifluoromethyl)benzonitrile[340]

To 337 (28.6 mg, 0.0615 mmol) was added 1-cyclopropylpiperazine (61.2mg, 0.3076 mmol) and Et₃N (100 μL) in DMF (1 mL) and heated at 90° C.for 1 h. Solvent was removed under reduced pressure and the residue waspurified by preparatory TLC (CH₂Cl₂:MeOH, 20:1) to afford 25.7 mg (75%)of 340. MS (ESI) m/z [M+H]⁺ 555.1.

4-((2-(4-(Cyclopropylmethyl)piperazin-1-yl)-4-((3-(dimethylamino)benzyl)oxy)pyrimidin-5-yl)thio)-2-(trifluoromethyl)benzonitrile[342]

To 337 (24.5 mg, 0.0527 mmol) was added 1-(cyclopropylmethyl)piperazine(36.9 mg, 0.263 mmol) and Et₃N (50 μL) in DMF (1 mL) and heated at 90°C. for 1 h. Solvent was removed under reduced pressure and the residuewas purified by preparatory TLC (CH₂Cl₂:MeOH, 20:1) to afford 23.7 mg(79%) of 342. MS (ESI) m/z [M+H]⁺ 569.1.

4-((4-((3-(Dimethylamino)benzyl)oxy)-2-(4-methyl-3-oxopiperazin-1-yl)pyrimidin-5-yl)thio)-2-(trifluoromethyl)benzonitrile[344]

To 337 (31.8 mg, 0.0684 mmol) was added 1-methylpiperazin-2-one (51.5mg, 0.342 mmol) and Et₃N (50 μL) in DMF (1 mL) and heated at 90° C. for1 h. Solvent was removed under reduced pressure and the residue waspurified by preparatory TLC (CH₂Cl₂:MeOH, 20:1) to afford 31.8 mg (86%)of 344. MS (ESI) m/z [M+H]⁺ 543.1.

4-((4-((3-(Dimethylamino)benzyl)oxy)-2-(4-(prop-2-yn-1-yl)piperazin-1-yl)pyrimidin-5-yl)thio)-2-(trifluoromethyl)benzamide[339]

A mixture of 338 (19.7 mg, 0.0356 mmol) and KOH (40 mg, 0.713 mmol) int-BuOH (2 mL) was heated at 80° C. for 1.5 h. Solvent was removed underreduced pressure and the residue was purified by preparatory TLC(CH₂Cl₂:MeOH—NH₃ (7 N), 20:1) to afford 7.8 mg (38%) of 339. ¹H NMR (600MHz, CDCl₃): δ 8.25 (s, 1H), 7.44 (s, 1H), 7.31 (d, J=8.1 Hz, 1H), 7.14(t, J=7.8 Hz, 1H), 7.11 (d, J=8.1 Hz, 1H), 6.64 (d, J=8.3 Hz, 1H),6.55-6.58 (m, 2H), 5.93 (br s, 1H), 5.79 (br s, 1H), 5.33 (s, 2H),3.92-3.95 (m, 4H), 3.39 (s, 2H), 2.82 (s, 6H), 2.64-2.66 (m, 4H), 2.28(t, J=2.3 Hz, 1H); ¹³C NMR (150 MHz, CDCl₃): 169.2, 168.7, 164.9, 161.7,150.6, 142.2, 136.9, 131.2, 129.1, 129.0, 128.8, 127.6 (q, J=31.9 Hz),123.7 (q, J=5.0 Hz), 123.2 (q, J=272.3 Hz), 116.1, 112.4, 111.9, 97.0,78.3, 73.6, 68.4, 51.6, 46.9, 43.8, 40.6; HRMS (ESI) m/z [M+H]⁺ calcd.for C₂₈H₃₀F₃N₆O₂S, 571.2103; found 571.2086.

4-((2-(4-Cyclopropylpiperazin-1-yl)-4-((3-(dimethylamino)benzyl)oxy)pyrimidin-5-yl)thio)-2-(trifluoromethyl)benzamide[341]

A mixture of 340 (25.7 mg, 0.0463 mmol) and KOH (52 mg, 0.927 mmol) int-BuOH (2 mL) was heated at 80° C. for 1.5 h. Solvent was removed underreduced pressure and the residue was purified by preparatory TLC(CH₂Cl₂:MeOH—NH₃ (7 N), 20:1) to afford 19 mg (72%) of 341. ¹H NMR (600MHz, CDCl₃): δ 8.25 (s, 1H), 7.45 (s, 1H), 7.31 (d, J=8.1 Hz, 1H), 7.14(t, J=7.9 Hz, 1H), 7.10 (dd, J=8.1, 1.4 Hz, 1H), 6.65 (dd, J=8.2, 2.2Hz, 1H), 6.55-6.59 (m, 2H), 5.93 (s, 1H), 5.84 (s, 1H), 5.34 (s, 2H),3.86 (m, 4H), 2.83 (s, 6H), 2.69 (m, 4H), 1.63-1.69 (m, 1H), 0.46-0.53(m, 4H); ¹³C NMR (150 MHz, CDCl₃): δ 169.3, 168.7, 164.9, 161.7, 150.6,142.3, 137.0, 131.2, 129.05, 128.99, 128.8, 127.6 (q, J=31.9 Hz), 123.7(q, J=5.0 Hz), 123.2 (q, J=272.3 Hz), 116.1, 112.4, 112.0, 96.7, 68.3,53.1, 43.9, 40.6, 38.5, 5.9; HRMS (ESI) m/z [M+H]⁺ calcd. forC₂₈H₃₂F₃N₆O₂S, 573.2260; found 573.2264.

4-((2-(4-(Cyclopropylmethyl)piperazin-1-yl)-4-((3-(dimethylamino)benzyl)oxy)pyrimidin-5-yl)thio)-2-(trifluoromethyl)benzamide[343]

A mixture of 342 (23.7 mg, 0.0417 mmol) and KOH (46.8 mg, 0.833 mmol) int-BuOH (2 mL) was heated at 80° C. for 1.5 h. Solvent was removed underreduced pressure and the residue was purified by preparatory TLC(CH₂Cl₂:MeOH—NH₃ (7 N), 20:1) to afford 15.4 mg (63%) of 343. ¹H NMR(600 MHz, CDCl₃): δ 8.25 (s, 1H), 7.45 (s, 1H), 7.31 (d, J=8.1 Hz, 1H),7.14 (t, J=7.9 Hz, 1H), 7.10 (dd, J=8.0, 1.5 Hz, 1H), 6.64 (dd, J=8.2,2.3 Hz, 1H), 6.55-6.59 (m, 2H), 5.94 (s, 1H), 5.88 (s, 1H), 5.34 (s,2H), 3.93 (m, 4H), 2.83 (s, 6H), 2.61 (m, 4H), 2.33 (d, J=6.6 Hz, 2H),0.88-0.95 (m, 1H), 0.54-0.59 (m, 2H), 0.13-0.16 (m, 2H); ¹³C NMR (150MHz, CDCl₃): δ 169.3, 168.7, 164.9, 161.7, 150.6, 142.2, 137.0, 131.2,129.1, 129.0, 128.8, 127.6 (q, J=31.8 Hz), 123.7 (q, J=5.0 Hz), 123.2(q, J=272.4 Hz), 116.1, 112.4, 112.0, 96.7, 68.3, 63.8, 53.0, 43.9,40.6, 8.3, 4.0; HRMS (ESI) m/z [M+H]⁺ calcd. for C₂₉H₃₄F₃N₆O₂S,587.2416; found 587.2416.

4-((4-((3-(Dimethylamino)benzyl)oxy)-2-(4-methyl-3-oxopiperazin-1-yl)pyrimidin-5-yl)thio)-2-(trifluoromethyl)benzamide[345]

A mixture of 344 (31.8 mg, 0.0586 mmol) and KOH (65.8 mg, 1.172 mmol) int-BuOH (2 mL) was heated at 80° C. for 1.5 h. Solvent was removed underreduced pressure and the residue was purified by preparatory TLC(CH₂Cl₂:MeOH—NH₃ (7 N), 20:1) to afford 22.7 mg (69%) of 345. ¹H NMR(600 MHz, CDCl₃): δ 8.29 (s, 1H), 7.44 (s, 1H), 7.33 (d, J=8.1 Hz, 1H),7.15 (t, J=7.9 Hz, 1H), 7.12 (d, J=8.1 Hz, 1H), 6.65 (d, J=8.3 Hz, 1H),6.58 (s, 1H), 6.54 (d, J=7.5 Hz, 1H), 5.92 (br s, 1H), 5.68 (br s, 1H),5.35 (s, 2H), 4.47 (s, 2H), 4.11-4.14 (m, 2H), 3.45-3.47 (m, 2H), 3.06(s, 3H), 2.85 (s, 6H); HRMS (ESI) m/z [M+H]⁺ calcd. for C₂₆H₂₈F₃N₆O₃S,561.1896; found 561.1902.

Example 40

4-((4-((3-Chlorobenzyl)oxy)-2-(4-(prop-2-yn-1-yl)piperazin-1-yl)pyrimidin-5-yl)thio)benzonitrile[347]

To 346 (24.2 mg, 0.0623 mmol) was added 1-(prop-2-yn-1-yl)piperazine(68.9 mg, 0.3116 mmol) and Et₃N (50 μL) in DMF (1 mL) and heated at 90°C. for 1 h. Solvent was removed under reduced pressure and the residuewas purified by preparatory TLC (CH₂Cl₂:MeOH, 40:1) to afford 17.5 mg(59%) of 347. MS (ESI) m/z [M+H]⁺ 476.0.

4-((4-((3-Chlorobenzyl)oxy)-2-(4-(prop-2-yn-1-yl)piperazin-1-yl)pyrimidin-5-yl)thio)benzamide[348]

A mixture of 347 (17.5 mg, 0.0368 mmol) and KOH (41.3 mg, 0.735 mmol) int-BuOH (2 mL) was heated at 80° C. for 1.5 h. Solvent was removed underreduced pressure and the residue was purified by preparatory TLC(CH₂Cl₂:MeOH—NH₃ (7 N), 20:1) to afford 9.4 mg (52%) of 348. ¹H NMR (600MHz, CDCl₃): δ 8.27 (s, 1H), 7.66 (d, J=8.4 Hz, 2H), 7.17-7.32 (m, 2H),7.14 (d, J=8.4 Hz, 2H), 7.09 (s, 1H), 7.02 (d, J=7.5 Hz, 1H), 6.01 (brs, 1H), 5.61 (br s, 1H), 5.31 (s, 2H), 3.98-4.02 (m, 4H), 3.38 (s, 2H),2.60-2.65 (m, 4H), 2.28 (t, J=2.3 Hz, 1H); ¹³C NMR (150 MHz, CDCl₃): δ168.7, 168.3, 164.9, 161.5, 143.4, 138.4, 134.2, 129.9, 129.6, 128.0,127.8, 127.4, 125.9, 125.4, 97.9, 78.4, 73.7, 66.9, 51.6, 46.8, 43.8;HRMS (ESI) m/z [M+H]⁺ calcd. for C₂₅H₂₅ClN₅O₂S, 494.1417; found494.1411.

Example 41

4-((4-((3-Chlorobenzyl)oxy)-2-(4-(prop-2-yn-1-yl)piperazin-1-yl)pyrimidin-5-yl)thio)-2-(trifluoromethyl)benzonitrile[350]

To 349 (12.5 mg, 0.0274 mmol) was added 1-(prop-2-yn-1-yl)piperazine(30.3 mg, 0.137 mmol) and Et₃N (50 μL) in DMF (1 mL) and heated at 90°C. for 1 h. Solvent was removed under reduced pressure and the residuewas purified by preparatory TLC (CH₂Cl₂:MeOH, 40:1) to afford 12.5 mg(84%) of 350. MS (ESI) m/z [M+H]⁺ 544.0.

4-((4-((3-Chlorobenzyl)oxy)-2-(4-(prop-2-yn-1-yl)piperazin-1-yl)pyrimidin-5-yl)thio)-2-(trifluoromethyl)benzamide[351]

A mixture of 350 (12.5 mg, 0.023 mmol) and KOH (26 mg, 0.459 mmol) int-BuOH (2 mL) was heated at 80° C. for 1.5 h. Solvent was removed underreduced pressure and the residue was purified by preparatory TLC(CH₂Cl₂:MeOH—NH₃ (7 N), 20:1) to afford 6.2 mg (48%) of 351. ¹H NMR (600MHz, CDCl₃): δ 8.27 (s, 1H), 7.40-7.45 (m, 2H), 7.20-7.25 (m, 3H), 7.14(s, 1H), 7.04 (d, J=6.7 Hz, 1H), 5.79 (br s, 2H), 5.32 (s, 2H),3.88-3.92 (m, 4H), 3.38 (s, 2H), 2.62-2.65 (m, 4H), 2.28 (t, J=2.2 Hz,1H); ¹³C NMR (150 MHz, CDCl₃): δ 169.1, 168.3, 165.1, 161.6, 142.0,138.2, 134.2, 131.4, 129.8, 129.2, 129.1, 128.1, 127.7 (q, J=31.9 Hz),127.5, 125.4, 123.8 (q, J=5.1 Hz), 123.2 (q, J=272.3 Hz), 96.9, 78.3,73.6, 67.0, 51.5, 46.9, 43.8; HRMS (ESI) m/z [M+H]⁺ calcd. forC₂₆H₂₄ClF₃N₅O₂S, 562.1291; found 562.1298.

Example 42

4-((4-((3-Chloro-4-fluorobenzyl)oxy)-2-(4-(prop-2-yn-1-yl)piperazin-1-yl)pyrimidin-5-yl)thio)benzonitrile[353]

To 352 (24.7 mg, 0.0608 mmol) was added 1-(prop-2-yn-1-yl)piperazine(67.2 mg, 0.304 mmol) and Et₃N (100 μL) in DMF (1 mL) and heated at 90°C. for 1 h. Solvent was removed under reduced pressure and the residuewas purified by preparatory TLC (CH₂Cl₂:MeOH, 40:1) to afford 24.5 mg(82%) of 353. MS (ESI) m/z [M+H]⁺ 494.0.

4-((4-((3-Chloro-4-fluorobenzyl)oxy)-2-(4-(prop-2-yn-1-yl)piperazin-1-yl)pyrimidin-5-yl)thio)benzamide[354]

A mixture of 353 (24.5 mg, 0.05 mmol) and KOH (56 mg, 0.99 mmol) int-BuOH (2 mL) was heated at 80° C. for 1.5 h. Solvent was removed underreduced pressure and the residue was purified by preparatory TLC(CH₂Cl₂:MeOH—NH₃ (7 N), 20:1) to afford 19.1 mg (75%) of 354. ¹H NMR(600 MHz, CDCl₃): δ 8.28 (s, 1H), 7.67 (d, J=8.4 Hz, 2H), 7.14 (d, J=7.0Hz, 1H), 7.12 (d, J=8.4 Hz, 2H), 6.98-7.03 (m, 2H), 6.02 (br s, 1H),5.70 (br s, 1H), 5.27 (s, 2H), 3.90-3.95 (m, 4H), 3.39 (s, 2H),2.62-2.66 (m, 4H), 2.29 (t, J=2.3 Hz, 1H); ¹³C NMR (150 MHz, CDCl₃): δ168.4 (d, J=52.7 Hz), 165.0, 161.4, 158.4, 156.8, 143.4, 133.4, 130.1,129.7, 127.9, 127.2 (d, J=11.9 Hz), 125.9, 120.9 (d, J=17.9 Hz), 116.4(d, J=23.9 Hz), 98.0, 78.3, 73.8, 66.5, 51.7, 47.2, 43.9; HRMS (ESI) m/z[M+H]⁺ calcd. for C₂₅H₂₄ClFN₅O₂S, 512.1323; found 512.1330.

Example 43

4-((4-((3-Iodobenzyl)oxy)-2-(4-(prop-2-yn-1-yl)piperazin-1-yl)pyrimidin-5-yl)thio)-2-(trifluoromethyl)benzonitrile[356]

To 355 (46.7 mg, 0.0853 mmol) was added 1-(prop-2-yn-1-yl)piperazine(94.3 mg, 0.426 mmol) and Et₃N (100 μL) in DMF (1 mL) and heated at 90°C. for 1 h. Solvent was removed under reduced pressure and the residuewas purified by preparatory TLC (CH₂Cl₂:MeOH, 40:1) to afford 37.5 mg(69%) of 356. MS (ESI) m/z [M+H]⁺ 636.2.

4-((4-((3-Iodobenzyl)oxy)-2-(4-(prop-2-yn-1-yl)piperazin-1-yl)pyrimidin-5-yl)thio)-2-(trifluoromethyl)benzamide[357]

A mixture of 356 (37.5 mg, 0.059 mmol) and KOH (66.2 mg, 1.18 mmol) int-BuOH (2 mL) was heated at 80° C. for 1.5 h. Solvent was removed underreduced pressure and the residue was purified by preparatory TLC(CH₂Cl₂:MeOH—NH₃ (7 N), 20:1) to afford 21.7 mg (56%) of 357. ¹H NMR(600 MHz, CDCl₃): δ 8.28 (s, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.58 (s, 1H),7.43-7.47 (m, 2H), 7.21 (d, J=8.1 Hz, 1H), 7.11 (d, J=7.7 Hz, 1H), 7.03(t, J=7.7 Hz, 1H), 5.80 (br s, 1H), 5.78 (br s, 1H), 5.29 (s, 2H),3.89-3.92 (m, 4H), 3.39 (s, 2H), 2.63-2.66 (m, 4H), 2.28 (t, J=2.4 Hz,1H); ¹³C NMR (150 MHz, CDCl₃): δ 169.0, 168.4, 165.1, 161.6, 142.1,138.6, 136.9, 136.4, 131.4, 130.3, 129.3, 128.9, 127.7 (q, J=31.9 Hz),126.5, 123.8 (q, J=5.2 Hz), 123.2 (q, J=272.6 Hz), 96.9, 94.1, 78.3,73.6, 66.9, 51.5, 46.9, 43.8; HRMS (ESI) m/z [M+H]⁺ calcd. forC₂₆H₂₄F₃IN₅O₂S, 654.0648; found 654.0644.

Example 44

4-((4-((3-Iodobenzyl)oxy)-2-(4-(4-((tetrahydro-2H-pyran-2-yl)oxy)but-2-yn-1-yl)piperazin-1-yl)pyrimidin-5-yl)thio)-2-(trifluoromethyl)benzonitrile[358]

To 355 (45.8 mg, 0.0836 mmol) was added1-(4-((tetrahydro-2H-pyran-2-yl)oxy)but-2-yn-1-yl)piperazine (79.7 mg,0.33 mmol) and Et₃N (100 μL) in DMF (1 mL) and heated at 90° C. for 1 h.Solvent was removed under reduced pressure and the residue was purifiedby preparatory TLC (hexane:EtOAc, 1:4) to afford 45.9 mg (73%) of 358.MS (ESI) m/z [M+H]⁺ 750.2.

4-((4-((3-Iodobenzyl)oxy)-2-(4-(4-((tetrahydro-2H-pyran-2-yl)oxy)but-2-yn-1-yl)piperazin-1-yl)pyrimidin-5-yl)thio)-2-(trifluoromethyl)benzamide[359]

A mixture of 358 (45.9 mg, 0.0612 mmol) and KOH (68.7 mg, 1.22 mmol) int-BuOH (2 mL) was heated at 70° C. for 1.5 h. Solvent was removed underreduced pressure and the residue was purified by preparatory TLC(CH₂Cl₂:MeOH—NH₃ (7 N), 15:1) to afford 22.9 mg (49%) of 359. MS (ESI)m/z [M+H]⁺ 768.1.

4-((2-(4-(4-Hydroxybut-2-yn-1-yl)piperazin-1-yl)-4-((3-iodobenzyl)oxy)pyrimidin-5-yl)thio)-2-(trifluoromethyl)benzamide[360]

A mixture of 359 (22.9 mg, 0.03 mmol) in EtOH (1 mL) was added PPTS (1mg, 0.004 mmol) and the reaction stirred at 60° C. for overnight.Solvent was removed under reduced pressure and the residue was purifiedby preparatory TLC (CH₂Cl₂:MeOH—NH₃ (7 N), 10:1) to afford 12.0 mg (59%)of 360. ¹H NMR (600 MHz, CDCl₃): δ 8.27 (s, 1H), 7.57-7.61 (m, 2H),7.44-7.47 (m, 2H), 7.21 (d, J=8.0 Hz, 1H), 7.11 (d, J=7.7 Hz, 1H), 7.03(t, J=7.7, 1H), 5.78 (br s, 2H), 5.29 (s, 2H), 4.31 (s, 2H), 3.89-3.95(m, 4H), 3.41 (s, 2H), 2.61-2.65 (m, 4H); ¹³C NMR (150 MHz, CDCl₃): δ169.0, 168.4, 165.1, 161.6, 142.1, 138.5, 136.9, 136.4, 131.4, 130.3,129.3, 129.0, 127.7 (q, J=31.9 Hz), 126.6, 123.8 (q, J=5.0 Hz), 123.2(q, J=272.4 Hz), 96.9, 94.1, 83.7, 80.5, 66.9, 51.7, 51.2, 47.3, 43.8;HRMS (ESI) m/z [M+H]⁺ calcd. for C₂₇H₂₆F₃IN₅O₃S, 684.0753; found684.0753.

Example 45

(R)-4-((2-(3-(Dimethylamino)pyrrolidin-1-yl)-4-((3-fluorobenzyl)oxy)pyrimidin-5-yl)thio)benzonitrile[362]

To (3-fluorophenyl)methanol (34 μL, 0.311 mmol) dissolved in CH₃CN (3mL) was added NaH (7.0 mg, 0.292 mmol) and the resulting suspension wasstirred for 10 min. at rt. Then 361 (26.3 mg, 0.0731 mmol) was added andthe reaction mixture was stirred at rt for 3 h. The reaction mixture wasconcentrated under reduced pressure to give a residue which was purifiedby preparatory TLC (CH₂Cl₂:MeOH—NH₃ (7 N), 40:1) to afford 24.8 mg (77%)of 362. MS (ESI) m/z [M+H]⁺ 450.0.

(R)-4-((4-((3-Chlorobenzyl)oxy)-2-(3-(dimethylamino)pyrrolidin-1-yl)pyrimidin-5-yl)thio)benzonitrile[364]

To (3-chlorophenyl)methanol (35 μL, 0.296 mmol) dissolved in CH₃CN (3mL) was added NaH (6.7 mg, 0.279 mmol) and the resulting suspension wasstirred for 10 min. at rt. Then 361 (25.1 mg, 0.07 mmol) was added andthe reaction mixture was stirred at rt for 3 h. The reaction mixture wasconcentrated under reduced pressure to give a residue which was purifiedby preparatory TLC (CH₂Cl₂:MeOH—NH₃ (7 N), 40:1) to afford 22.6 mg (69%)of 364. MS (ESI) m/z [M+H]⁺ 466.0.

(R)-4-((4-((3-Bromobenzyl)oxy)-2-(3-(dimethylamino)pyrrolidin-1-yl)pyrimidin-5-yl)thio)benzonitrile[366]

To (3-bromophenyl)methanol (35 μL, 0.296 mmol) dissolved in CH₃CN (3 mL)was added NaH (6.7 mg, 0.279 mmol) and the resulting suspension wasstirred for 10 min. at rt. Then 361 (25.1 mg, 0.07 mmol) was added andthe reaction mixture was stirred at rt for 3 h. The reaction mixture wasconcentrated under reduced pressure to give a residue which was purifiedby preparatory TLC (CH₂Cl₂:MeOH—NH₃ (7 N), 40:1) to afford 29.3 mg (82%)of 366. MS (ESI) m/z [M+H]⁺ 510.0/512.0.

(R)-4-((2-(3-(Dimethylamino)pyrrolidin-1-yl)-4-((3-iodobenzyl)oxy)pyrimidin-5-yl)thio)benzonitrile[368]

To a solution of (3-iodophenyl)methanol (40 μL, 0.311 mmol) in CH₃CN (3mL) was added NaH (7.0 mg, 0.292 mmol) and the resulting suspension wasstirred for 10 min. at rt. Then 361 (26.3 mg, 0.0731 mmol) was added andthe reaction mixture was stirred at rt for 3 h. The reaction mixture wasconcentrated under reduced pressure to give a residue which was purifiedby preparatory TLC (CH₂Cl₂:MeOH—NH₃ (7 N), 40:1) to afford 33.8 mg (83%)of 368. MS (ESI) m/z [M+H]⁺ 558.1.

(R)-4-((2-(3-(Dimethylamino)pyrrolidin-1-yl)-4-((3-fluorobenzyl)oxy)pyrimidin-5-yl)thio)benzamide[363]

A mixture of 362 (24.8 mg, 0.0552 mmol) and KOH (61.91 mg, 1.1033 mmol)in t-BuOH (2 mL) was heated at 70° C. for 1.5 h. Solvent was removedunder reduced pressure and the residue was purified by preparatory TLC(CH₂Cl₂:MeOH—NH₃ (7 N), 15:1) to afford 21.1 mg (82%) of 363. ¹H NMR(600 MHz, CDCl₃): δ 8.29 (s, 1H), 7.65 (d, J=8.4 Hz, 2H), 7.18-7.23 (m,1H), 7.12 (d, J=8.4 Hz, 2H), 6.89-6.94 (m, 2H), 6.75 (d, J=9.2 Hz, 1H),6.05 (br s, 1H), 5.72 (br s, 1H), 5.35 (s, 2H), 3.93-3.97 (m, 1H),3.79-3.86 (m, 1H), 3.48-3.53 (m, 1H), 3.30-3.37 (m, 1H), 2.79-2.82 (m,1H), 2.33 (s, 6H), 2.20-2.25 (m, 1H), 1.90-1.95 (m, 1H); ¹³C NMR (150MHz, CDCl₃): δ 168.8, 168.2, 164.9, 163.5, 161.9, 160.2, 143.6, 139.2,129.8 (d, J=27.8 Hz), 127.8, 125.9, 122.9, 114.6 (d, J=24.9 Hz), 114.2(d, J=27.8 Hz), 97.6, 66.8, 65.3, 51.3, 45.9, 44.3, 30.1; MS (ESI) m/z[M+H]⁺ 468.1.

(R)-4-((4-((3-Chlorobenzyl)oxy)-2-(3-(dimethylamino)pyrrolidin-1-yl)pyrimidin-5-yl)thio)benzamide[365]

A mixture of 364 (22.6 mg, 0.0485 mmol) and KOH (54.43 mg, 0.97 mmol) int-BuOH (2 mL) was heated at 70° C. for 1.5 h. Solvent was removed underreduced pressure and the residue was purified by preparatory TLC(CH₂Cl₂:MeOH—NH₃ (7 N), 15:1) to afford 17.4 mg (74%) of 365. ¹H NMR(600 MHz, CDCl₃): δ 8.29 (s, 1H), 7.66 (d, J=8.4 Hz, 2H), 7.21-7.22 (m,1H), 7.17 (t, J=7.6 Hz, 1H), 7.10-7.13 (m, 3H), 7.02 (d, J=7.3 Hz, 1H),6.04 (br s, 1H), 5.69 (br s, 1H), 5.33 (s, 2H), 3.93-3.97 (m, 1H),3.79-3.87 (m, 1H), 3.47-3.53 (m, 1H), 3.29-3.37 (m, 1H), 2.79-2.82 (m,1H), 2.34 (d, J=9.4 Hz, 6H), 2.21-2.25 (m, 1H), 1.88-1.96 (m, 1H); ¹³CNMR (150 MHz, CDCl₃): δ 168.8, 168.2, 164.9, 160.2, 143.6, 138.7, 134.2,129.9, 129.6, 127.9, 127.8, 127.6, 125.8, 125.6, 97.4, 66.9, 65.3, 51.2,45.9, 44.3, 30.2; HRMS (ESI) m/z [M+H]⁺ calcd. for C₂₄H₂₇ClN₅O₂S,484.1574; found 484.1588.

(R)-4-((4-((3-Bromobenzyl)oxy)-2-(3-(dimethylamino)pyrrolidin-1-yl)pyrimidin-5-yl)thio)benzamide[367]

A mixture of 366 (29.3 mg, 0.0574 mmol) and KOH (64.4 mg, 1.148 mmol) int-BuOH (2 mL) was heated at 70° C. for 1.5 h. Solvent was removed underreduced pressure and the residue was purified by preparatory TLC(CH₂Cl₂:MeOH—NH₃ (7 N), 15:1) to afford 15.9 mg (52%) of 367. ¹H NMR(600 MHz, CDCl₃): δ 8.29 (s, 1H), 7.66 (d, J=8.4 Hz, 2H), 7.36 (d, J=7.8Hz, 1H), 7.29 (s, 1H), 7.06-7.13 (m, 4H), 6.04 (br s, 1H), 5.67 (br s,1H), 5.32 (s, 2H), 3.93-3.97 (m, 1H), 3.79-3.87 (m, 1H), 3.49-3.53 (m,1H), 3.30-3.36 (m, 1H), 2.78-2.82 (m, 1H), 2.34 (d, J=10.9 Hz, 6H),2.22-2.25 (m, 1H), 1.90-1.95 (m, 1H); ¹³C NMR (150 MHz, CDCl₃): δ 168.7,168.2, 164.9, 160.2, 143.6, 138.9, 130.9, 130.6, 130.5, 129.9, 127.8,126.1, 125.7, 122.3, 97.3, 66.8, 65.3, 51.2, 45.9, 44.3, 30.4; HRMS(ESI) m/z [M+H]⁺ calcd. for C₂₄H₂₇BrN₅O₂S, 528.1069; found 528.1052.

(R)-4-((2-(3-(Dimethylamino)pyrrolidin-1-yl)-4-((3-iodobenzyl)oxy)pyrimidin-5-yl)thio)benzamide[369]

A mixture of 368 (33.8 mg, 0.0606 mmol) and KOH (68.04 mg, 1.212 mmol)in t-BuOH (2 mL) was heated at 70° C. for 1.5 h. Solvent was removedunder reduced pressure and the residue was purified by preparatory TLC(CH₂Cl₂:MeOH—NH₃ (7 N), 15:1) to afford 18.8 mg (54%) of 369. ¹H NMR(600 MHz, CDCl₃): δ 8.28 (s, 1H), 7.67 (d, J=8.3 Hz, 2H), 7.57 (d, J=7.9Hz, 1H), 7.53 (s, 1H), 7.08-7.18 (m, 3H), 6.98 (t, J=7.7 Hz, 1H), 6.07(s, 1H), 5.77 (s, 1H), 5.30 (s, 2H), 3.95 (m, 1H), 3.84 (m, 1H), 3.51(m, 1H), 3.33 (m, 1H), 2.80 (m, 1H), 2.34 (d, J=13.4 Hz, 6H), 2.23 (m,1H), 1.92 (m, 1H); HRMS (ESI) m/z [M+H]⁺ calcd. for C₂₄H₂₇IN₅O₂S,576.0930; found 576.0952.

Example 46

(R)-1-(4-(Benzyloxy)-5-((6-nitropyridin-3-yl)thio)pyrimidin-2-yl)-N,N-dimethylpyrrolidin-3-amine[371]

A mixture of 370 (0.768 g, 1.69 mmol) and K₂CO₃ (0.701 g, 5.07 mmol) inDMF (5 mL) was evacuated and backfilled with argon three times.Copper(I)thiophene-2-carboxylate (0.129 g, 0.676 mmol) was added andevacuated and backfilled with argon two times. 6-Nitropyridine-3-thiol(0.343 g, 2.2 mmol) was added and the reaction mixture was heated at120° C. for 20 h. Solvent was removed under reduced pressure and theresidue was purified by column chromatography (CH₂Cl₂:MeOH, 200:1 to40:1) to afford 0.649 g (80%) of 371. MS (ESI) m/z [M+H]⁺ 483.2.

(R)-2-(3-(Dimethylamino)pyrrolidin-1-yl)-5-((6-nitropyridin-3-yl)thio)pyrimidin-4-ol[372]

To a solution of 371 (0.649 g, 1.34 mmol) in CH₂Cl₂ (4 mL) was added TFA(4 mL) dropwise over 5 minutes and stirred at rt for 16 h. The reactionmixture was concentrated under reduced pressure to give a residue whichwas purified by column chromatography (CH₂Cl₂:MeOH, 9:1 to 8:2) toafford 0.351 g (72%) of 372. MS (ESI) m/z [M+H]⁺ 363.2.

(R)-1-(4-Chloro-5-((6-nitropyridin-3-yl)thio)pyrimidin-2-yl)-N,N-dimethylpyrrolidin-3-amine[373]

372 (0.351 g, 0.968 mmol), POCl₃ (3.4 mL) and DIEA (0.423 mL, 2.42 mmol)were heated at 75° C. for 1 h. After cooling to rt, the reaction mixturewas added to a beaker containing ice chips. Following complete quenchingof POCl₃, solid Na₂CO₃ was carefully added until pH˜9. This wastransferred to a seperatory funnel and extracted with CH₂Cl₂ (4×50 mL),dried over MgSO₄, filtered and concentrated to a solid which waspurified by column chromatography (CH₂Cl₂:MeOH, 100:0 to 95:5) to afford139.5 mg (38%) of 373. MS (ESI) m/z [M+H]⁺ 381.0.

(R)-5-((4-Chloro-2-(3-(dimethylamino)pyrrolidin-1-yl)pyrimidin-5-yl)thio)pyridin-2-amine[374]

A mixture of 373 (139.5 mg, 0.366 mmol) and iron powder (82 mg, 1.465mmol) in acetic acid (1 mL) was stirred at rt for overnight. Thereaction mixture was concentrated under reduced pressure and purified bycolumn chromatography (CH₂Cl₂:MeOH, 100:0 to 90:10) to afford 78.1 mg(61%) of 374. MS (ESI) m/z [M+H]⁺ 351.1.

(R)-5-((2-(3-(Dimethylamino)pyrrolidin-1-yl)-4-((3-methoxybenzyl)oxy)pyrimidin-5-yl)thio)pyridin-2-amine[375]

To a solution of (3-methoxyphenyl)methanol (42 μL, 0.338 mmol) in CH₃CN(3 mL) was added NaH (9.5 mg, 0.394 mmol) and the resulting suspensionwas stirred for 10 min. at rt. Then 374 (39.5 mg, 0.113 mmol) was addedand the reaction mixture was stirred at rt for 3 h. The reaction mixturewas concentrated under reduced pressure to give a residue which waspurified by preparatory TLC (CH₂Cl₂:MeOH—NH₃ (7 N), 20:1) to afford 12mg (23%) of 375. ¹H NMR (600 MHz, CDCl₃): δ 8.23 (s, 1H), 8.13 (s, 1H),7.40 (dd, J=8.5, 2.3 Hz, 1H), 7.23 (t, J=7.9 Hz, 1H), 6.85-6.90 (m, 2H),6.82 (dd, J=8.3, 2.2 Hz, 1H), 6.34 (d, J=8.5 Hz, 1H), 5.37 (s, 2H), 4.45(s, 2H), 3.79 (s, 3H), 3.46 (m, 1H), 3.27 (m, 1H), 2.74 (m, 1H), 2.31(s, 6H), 2.19 (s, 1H), 1.76-1.88 (m, 3H); HRMS (ESI) m/z [M+H]⁺ calcd.for C₂₃H₂₉N₆O₂S, 453.2073; found 453.2051.

Example 47

(R)-5-((4-((3-Chlorobenzyl)oxy)-2-(3-(dimethylamino)pyrrolidin-1-yl)pyrimidin-5-yl)thio)pyridin-2-amine[376]

To a solution of (3-chlorophenyl)methanol (41 μL, 0.351 mmol) in CH₃CN(3 mL) was added NaH (9.8 mg, 0.410 mmol) and the resulting suspensionwas stirred for 10 min. at rt. Then 374 (41.1 mg, 0.117 mmol) was addedand the reaction mixture was stirred at rt for 3 h. The reaction mixturewas concentrated under reduced pressure to give a residue which waspurified by preparatory TLC (CH₂Cl₂:MeOH—NH₃ (7 N), 20:1) to afford 9 mg(17%) of 376. ¹H NMR (600 MHz, CDCl₃): δ 8.25 (s, 1H), 8.12 (s, 1H),7.39 (d, J=8.5 Hz, 1H), 7.22-7.26 (m, 3H), 7.13-7.16 (m, 1H), 6.37 (d,J=8.5 Hz, 1H), 5.34 (s, 2H), 4.46 (br s, 2H), 3.75-3.88 (m, 2H),3.41-3.44 (m, 1H), 3.25-3.28 (m, 1H), 2.73-2.79 (m, 1H), 2.31 (s, 6H),2.16-2.21 (m, 1H), 1.83-1.91 (m, 1H); HRMS (ESI) m/z [M+H]⁺ calcd. forC₂₂H₂₆ClN₆OS, 457.1577; found 457.1561.

Example 48

4-((4-((3-Chlorobenzyl)oxy)-2-(4-(4-((tetrahydro-2H-pyran-2-yl)oxy)but-2-yn-1-yl)piperazin-1-yl)pyrimidin-5-yl)thio)benzonitrile[377]

To 346 (24.9 mg, 0.065 mmol) was added1-(4-((tetrahydro-2H-pyran-2-yl)oxy)but-2-yn-1-yl)piperazine (55.5 mg,0.233 mmol) and Et₃N (100 μL) in DMF (1 mL) and heated at 90° C. for 1h. Solvent was removed under reduced pressure and the residue waspurified by preparatory TLC (hexane:EtOAc, 1:4) to afford 28.2 mg (73%)of 377. MS (ESI) m/z [M+H]⁺ 590.1.

4-((4-((3-Chlorobenzyl)oxy)-2-(4-(4-((tetrahydro-2H-pyran-2-yl)oxy)but-2-yn-1-yl)piperazin-1-yl)pyrimidin-5-yl)thio)benzamide[378]

A mixture of 377 (28.2 mg, 0.0478 mmol) and KOH (26.8 mg, 0.478 mmol) int-BuOH (2 mL) was heated at 70° C. for 1.5 h. Solvent was removed underreduced pressure and the residue was purified by preparatory TLC(CH₂Cl₂:MeOH—NH₃ (7 N), 15:1) to afford 22 mg (46%) of 378. MS (ESI) m/z[M+H]⁺ 608.3.

4-((4-((3-Chlorobenzyl)oxy)-2-(4-(4-hydroxybut-2-yn-1-yl)piperazin-1-yl)pyrimidin-5-yl)thio)benzamide[379]

A mixture of 378 (13.4 mg, 0.022 mmol) in EtOH (1 mL) was added PPTS (1mg, 0.004 mmol) and the reaction stirred at 60° C. for overnight.Solvent was removed under reduced pressure and the residue was purifiedby preparatory TLC (CH₂Cl₂:MeOH—NH₃ (7 N), 10:1) to afford 6.2 mg (54%)of 379. ¹H NMR (600 MHz, CDCl₃/MeOH-d₄): δ 8.26 (s, 1H), 7.74-7.77 (m,2H), 7.19-7.24 (m, 2H), 7.14 (d, J=8.8 Hz, 2H), 7.11 (m, 1H), 7.04 (m,1H), 5.34 (s, 2H), 4.23 (s, 2H), 3.91 (m, 4H), 3.41 (s, 2H), 2.66 (m,4H); ¹³C NMR (150 MHz, CDCl₃/MeOH-d₄): δ 171.3, 169.4, 165.4, 162.3,144.0, 139.6, 135.0, 131.2, 130.5, 129.0, 128.6, 128.1, 126.6, 126.2,99.5, 85.3, 79.4, 67.9, 52.3, 50.6, 47.6, 44.3; HRMS (ESI) m/z [M+H]⁺calcd. for C₂₆H₂₇ClN₅O₃S, 524.1523; found 524.1508.

Example 49 Caspase Cleavage Assay

Caspase3, 7 Activation.

MOLM-13 cells (30,000 cells/well) were plated in black 96-well plates(Corning Cat. #3603) in 40 μL of RPMI media, and left in an incubator(37° C., 5% CO₂) for up to 24 h. Cells were treated for 16 h withcompounds or DMSO (control) at desired concentrations in 50 μL of media.Drugs were added in triplicate wells. Following exposure of cells toHsp70 inhibitors, 50 μL of buffer containing 10 mM HEPES (pH 7.5), 2 mMEDTA, 0.1% CHAPS and the caspase substrate Z-DEVD-R110 at 25 μM wasadded to each well. Plates were incubated until the signal stabilizedand then the fluorescence signal of each well was measured in an AnalystGT microplate reader. The percentage increase in apoptotic cells wascalculated by comparison of the fluorescence reading obtained fromtreated versus control cells.

Exemplary results are described in Table 7, below.

TABLE 7 Exemplary results of caspase activation assay. Compounds c*  10C  11 B  13 C  29 C  30 C  32 B  36 D  37 C  43 C  44 C  45 B  47 C  49B  56 E  58 C  62 C  63 E  65 C  66 B  67 B  68 D  70 A  73 D  74 C  77B  78 C  79 B  80 C  81 D  83 C  84 B  92 C  93 D  96 C 100a A 100b B100c A 100d E 100e A 100f C 100g A 100h B 100i C 100j B 100m B 100n E100o E 100q C 100r D 100s B 100t C 100u C 100v E 100w C 100x A 101 A 102B 108 A 109 A 110 B 111 A 112 A 113 A 114 A 115 B 116 A 117 B 118 C 121B 122 B 123 B 124 A 125 A 126 B 127 C 131 A 132 A 133 A 134 B 135 B 136A 137 A 138 A 139 A 141 D 146c B 146e C 151 A 152 B 153 A 154 A 155 A156 B 157 A 158 A 167 E 168 E 179a E 179c E 182 E 185a D 185b D 185d C185e A 187 D 190a B 190b B 190e A 190g E 190h E 190j A 190k A 190m A190n B 190o A 190p A 190q A 190r B 190t A 190u A 190v A 193 E 195 E 198A 205 C 206 C 207 C 208 A 212 A 213 E 214 C 218 A 225 B 226 B 227 E 228A 229 B 282 E 283 E 284 C 299 B 304 E 311 E 313 E 315 D 317 E 319 E 321A 323 A 326 A 329 C 331 E 333 D 336 A 339 C 341 E 343 E 345 D 348 C 351D 354 A 357 B 360 B 363 B 365 B 367 B 369 B 375 A 376 A 379 A*Concentration at which 50% of the maximum signal was achieved. A: c <0.2 μM; B: 0.2 μM ≦ c < 0.4 μM; C: 0.4 μM ≦ c < 1.0 μM; D: 1.0 μM ≦ c <1.2 μM; and E: c ≧ 1.2 μM

Example 50 Effects of Hsp70 Inhibitors on Cells with Resistance to Hsp90 Inhibitor

Cell lines: MDA-MB-468 cells were obtained from the American TypeCulture Collection. DLBCL cells were described in Cerchietti L C, et al.BCL6 repression of EP300 in human diffuse large B cell lymphoma cellsprovides a basis for rational combinatorial therapy. J Clin Invest. Dec.1, 2010; 120(12): 4569-4582; and Cerchietti L C, et al. A purinescaffold Hsp90 inhibitor destabilizes BCL-6 and has specific antitumoractivity in BCL-6-dependent B cell lymphomas. Nat Med. 2009 December;15(12):1369-76. MDA-MB-468 cells were grown in DME/F12 with 10% FBS and1% penicillin and streptomycin. OCI-LY1R cells were developed bycontinuous incubation of OCI-LY1 cells with suboptimal concentrations ofPU-H71 (depicted below) with subsequent selection of resistant clones.OCI-LY1, OCI-LY1R and OCI-LY7 cells were cultured in IMDM supplementedwith 20% FBS, 1% glutamax and 1% penicillin and streptomycin. OCI-LY3,FARAGE, HBL1, Karpas422, MD901, U2932, SU-DHL4, SU-DHL6, RCK8 and TMD8cells were grown in RPMI with 10% FBS, 1% glutamax and 1% penicillin andstreptomycin.

Western blot: Cells were plated and treated next day with indicated drugconcentrations for 24h. Cells were collected and protein was extractedin 20 mM Tris pH 7.4, 25 mM NaCl, 1% NP-40 buffer. 30-50 μg of totalprotein was subjected to SDS-PAGE, transferred onto nitrocellulosemembrane and incubated with indicated antibodies. P-Akt, BID, Mcl1,Caspase 9, caspase 3, caspase 7 and Bcl-XL antibodies were purchasedfrom Cell Signaling Technology; Bax antibody from Santa CruzBiotechnology; cleaved PARP Ab from Promega; and β-actin Ab from Sigma.Blots were washed with TBS-0.1% Tween 20 and incubated with theappropriate HRP-conjugated secondary antibody. The chemiluminescentsignal was detected using the Enhanced Chemiluminescence DetectionSystem (Amersham Biosciences) according to the manufacturer'sinstructions.

Growth inhibition: 5,000 cells per well were plated in black 96-wellmicrotiter plates and treated next day with indicated compounds at 1/2serial dilutions. The plate was incubated for 72h after which growth wasmeasured using the CellTiter-Glo Luminescent Cell Viability Assay(Promega) according to manufacture's instructions. The percentage cellgrowth inhibition was calculated by comparing luminescence readingsobtained from treated versus control cells, accounting for initial cellpopulation. The luminescence signal in each well was measured using theAnalyst GT microplate reader (Molecular Devices).

It was surprisingly found that provided compounds of the presentinvention can activate caspases, induce cell death and inhibit cellgrowth in cancer cells resistant to Hsp90 inhibitors (FIG. 1).

While several embodiments of the present invention have been describedand illustrated herein, those of ordinary skill in the art will readilyenvision a variety of other means and/or structures for performing thefunctions and/or obtaining the results and/or one or more of theadvantages described herein, and each of such variations and/ormodifications is deemed to be within the scope of the present invention.More generally, those skilled in the art will readily appreciate thatall parameters, dimensions, materials, and configurations describedherein are meant to be exemplary and that the actual parameters,dimensions, materials, and/or configurations will depend upon thespecific application or applications for which the teachings of thepresent invention is/are used. Those skilled in the art will recognize,or be able to ascertain using no more than routine experimentation, manyequivalents to the specific embodiments of the invention describedherein. It is, therefore, to be understood that the foregoingembodiments are presented by way of example only and that, within thescope of the appended claims and equivalents thereto, the invention maybe practiced otherwise than as specifically described and claimed. Thepresent invention is directed to each individual feature, system,article, material, kit, and/or method described herein. In addition, anycombination of two or more such features, systems, articles, materials,kits, and/or methods, if such features, systems, articles, materials,kits, and/or methods are not mutually inconsistent, is included withinthe scope of the present invention.

The invention claimed is:
 1. A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein: X is N═ or CH═;X¹ is —N═ or —C(R⁵)═; R¹ is

R^(1a) is

or C₁₋₆ aliphatic optionally substituted with one or more groupsindependently selected from —OH, cyclopropyl, or 5-membered heteroarylhaving 1-2 heteroatoms independently selected from nitrogen, oxygen orsulfur; each R^(1b) is independently hydrogen, C₁₋₄ alkyl, or two R^(1b)groups are optionally taken together to form an oxo group; each ofR^(1c) and R^(1d) is independently hydrogen or C₁₋₄ alkyl; R² is—O—CH₂-Ring A, —NH—CH₂-Ring A, or —O—CH₂CH₂-Ring A; Ring A isunsubstituted phenyl, unsubstituted furanyl,

or pyridinyl optionally substituted with R^(A5); each of R^(A1) isindependently halogen, —CN, —C(O)N(R)₂, —N(R)₂, —OR, —C(O)R, —N₃, anoptionally substituted 5- or 6-membered heterocyclyl or heteroarylhaving one or two heteroatoms independently selected from nitrogen,oxygen, or sulfur, or C₁₋₄ alkyl optionally substituted with one or morehalogen; each R is independently hydrogen or C₁₋₄ alkyl optionallysubstituted with one or more halogen; R^(A2) is —Cl, —Br, —I, —CN,—C(O)N(R)₂, —N(R)₂, —OR, —C(O)R, —N₃, C₁₋₄ alkyl optionally substitutedwith one or more halogen, or an optionally substituted 5- or 6-memberedheterocyclyl or heteroaryl having one or two heteroatoms independentlyselected from nitrogen, oxygen or sulfur; n is 1 to 4; R^(A3) is —H or—F; R^(A4) is —F or —OR; R^(A5) is —OR or —N(R)₂; R³ is —C(O)N(R^(3a))₂,—OR^(3b), —C(O)H, —C(O)OR, or —N(R^(3c))₂; each R^(3a) is independentlyhydrogen or C₁ alkyl optionally substituted with one or more groupsindependently selected from halogen or 1-pyrrolidinyl; R^(3b) ishydrogen or C₁₋₄ alkyl optionally substituted with one or more groupsindependently selected from halogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, oxo, or—N(R)₂; each R^(3c) is independently hydrogen or C₁₋₄ alkyl optionallysubstituted with one or more groups independently selected from halogen,C₁₋₄ alkyl, C₁₋₄ haloalkyl, oxo, or —N(R)₂; R⁴ is R, halogen, or —N(R)₂;and R⁵ is hydrogen, methyl or —N(R)₂.
 2. The compound of claim 1,wherein X is —N═.
 3. The compound of claim 1, wherein X is —CH═.
 4. Thecompound of claim 1, wherein R³ is —C(O)NH₂.
 5. The compound of claim 1,wherein R³ is —N(R^(3c))₂.
 6. The compound of claim 1, wherein R⁴ is—CF₃.
 7. The compound of claim 1, wherein R⁴ is halogen.
 8. The compoundof claim 1, wherein X¹ is —C(R⁵)═.
 9. The compound of claim 1, whereinX¹ is —N═.
 10. A compound of formula II:

or a pharmaceutically acceptable salt thereof, wherein: Y is —S—, —O—,or —CR₂—; R¹ is

R^(1a) is

or C₁₋₆ aliphatic optionally substituted with one or more groupsindependently selected from —OH, cyclopropyl, or 5-membered heteroarylhaving 1-2 heteroatoms independently selected from nitrogen, oxygen, orsulfur; each R^(1b) is independently hydrogen, C₁₋₄ alkyl, or two R^(1b)groups are optionally taken together to form an oxo group; each ofR^(1c) and R^(1d) is independently hydrogen or C₁₋₄ alkyl; R² is—O—CH₂-Ring A, —NH—CH₂-Ring A, or —O—CH₂CH₂-Ring A; Ring A isunsubstituted phenyl, unsubstituted furanyl,

or pyridinyl optionally substituted with R^(A5); each of R^(A1) isindependently halogen, —CN, —C(O)N(R)₂, —N(R)₂, —OR, —C(O)R, —N₃, anoptionally substituted 5- or 6-membered heterocyclyl or heteroarylhaving one or two heteroatoms independently selected from nitrogen,oxygen, or sulfur, or C₁₋₄ alkyl optionally substituted with one or morehalogen; each R is independently hydrogen or C₁₋₄ alkyl optionallysubstituted with one or more halogen; R^(A2) is —Cl, —Br, —I, —CN,—C(O)N(R)₂, —N(R)₂, —OR, —C(O)R, —N₃, C₁₋₄ alkyl optionally substitutedwith one or more halogen, or an optionally substituted 5- or 6-memberedheterocyclyl or heteroaryl having one or two heteroatoms independentlyselected from nitrogen, oxygen or sulfur; n is 1 to 4; R^(A3) is —H or—F; R^(A4) is —F or —OR; R^(A5) is —OR or —N(R)₂; and Ring B is

thienyl optionally substituted with —C(O)R, or furanyl optionallysubstituted with —C(O)R.
 11. The compound of claim 1, wherein R¹ is


12. The compound of claim 1, wherein R² is —O—CH₂-Ring A.
 13. Thecompound of claim 1, wherein Ring A is phenyl,


14. A compound selected from the group consisting of

or a pharmaceutically acceptable salt thereof.
 15. A pharmaceuticalcomposition comprising a compound of claim 1 and a pharmaceuticallyacceptable carrier.
 16. A method of treating cancer in a patient in needthereof, the method comprising administering to the patient atherapeutically effective amount of a compound of claim 1 or acomposition thereof.
 17. A pharmaceutical composition comprising acompound of claim 10 and a pharmaceutically acceptable carrier.
 18. Amethod of treating cancer in a patient in need thereof, the methodcomprising administering to the patient a therapeutically effectiveamount of a compound of claim 10 or a composition thereof.